Academic Appointments

Administrative Appointments

  • Member, Stanford Neurosciences Institute (2013 - Present)
  • Member, Stanford Neuro-Oncology Program (2013 - Present)
  • Member, Stanford Bio-X Program (2013 - Present)
  • Member, Non-Human Use Radiation Safety Committee, Stanford University, Stanford, CA USA (2011 - Present)
  • Member, Administrative Panel on Radiological Safety, Stanford University, Stanford, CA USA (2009 - Present)
  • Member, Radioactive Drug Research Committee, Stanford University, Stanford, CA USA (2005 - Present)
  • Member, Molecular Imaging Program at Stanford (2005 - Present)
  • Head, Cyclotron Radiochemistry, Stanford University School of Medicine, Department of Radiology, Stanford, CA USA (2005 - Present)

Honors & Awards

  • Phi Beta Kappa, Indiana University, Bloomington, IN USA (1990)
  • "Excellence in Teaching" Award, Indiana University - Purdue University at Indianapolis, Indianapolis, IN USA (1998)
  • Physical Scientist Research Award, Indiana University School of Medicine, Department of Radiology, Indianapolis, IN USA (1998)
  • LBNL Research Fellowship, Lawrence Berkeley National Laboratory, Berkeley, CA USA (2001-2002)
  • NIH Intramural Research Fellowship, National Institutes of Health, Bethesda, MD USA (2002-2005)
  • NIH Fellow Award for Research Excellence, National Institutes of Health, Bethesda, MD USA (2003, 2004)

Professional Education

  • Ph.D., Purdue University, W. Lafayette, IN, Organic Chemistry/Radiochemistry (2000)
  • B.S. with Honors, Indiana University, Bloomington, IN, Chemistry (1991)

Research & Scholarship

Current Research and Scholarly Interests

Our group's primary objectives are:

1) Novel radioligand and radiotracer development.
We will develop novel PET (Positron Emission Tomography) imaging agents with MIPS and Stanford faculty as well as other outside collaborations including academia and pharmaceutical industry. Although my personal research interests will be to discover and design of candidate probes that target molecular targets in the brain, our group focus will primarily be on cancer biology and gene therapy. In conjunction with our state-of-the-art imaging facility, promising candidates will be evaluated by PET-CT/MR imaging in small animals and primates. Successful radioligands and/or radiotracers will be extended towards future human clinical applications.

2) Designing new radiolabeling techniques and methodologies.
We will aim to design new radiolabeling techniques and methodologies that may have utility for future radiopharmaceutical development in our lab and the general radiochemistry community.

3) Radiochemistry production of routine clinical tracers.
Since we also have many interests with many Stanford faculty and outside collaborators, our efforts will also include the routine radiochemistry production of many existing radiotracers for human and non-human use. Our routine clinical tracers will be synthesized in custom-made or commercial synthetic modules (i.e. GE TRACERlab modules) housed in lead-shielded cells and be distributed manually or automatically (i.e. Comecer Dorothea) to our imagers.

Clinical Trials

  • Assessing the Suitability of an Imaging Probe for Use in Clinical Cell and Gene Therapy Trials in Cancer and Rheumatoid Arthritis Not Recruiting

    The purpose of this study is to determine whether [18F]FHBG is suitable for use as an imaging probe in cancer or rheumatoid arthritis patients enrolled in cell or gene therapy trials. In this phase 1 study we will assess the safety and biodistribution of [18F]FHBG in patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shahriar Shah Yaghoubi, Ph.D, 650-725-6070.

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  • 18F-FDOPA PET/CT or PET/MRI in Measuring Tumors in Patients With Newly-Diagnosed or Recurrent Gliomas Not Recruiting

    To evaluate 18F-FDOPA PET obtained from PET/CT or PET/MRI imaging in patients with newly diagnosed or recurrent gliomas.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrei Iagaru, 650-736-2859.

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  • 68Ga DOTA-TATE PET/CT in Somatostatin Receptor Positive Tumors Recruiting

    The primary objective of the study is to evaluate 68Ga-DOTA TATE PET/CT for staging and monitoring response to chemotherapy in patients with carcinoid, neuroendocrine tumors, medullary thyroid cancer and other cancers expressing somatostatin receptors.

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  • Exploration of Tumor Accumulation of BAY94-9392 in Patients With Cancer Not Recruiting

    The study will be conducted as an open label, single-dose, explorative study with patients with histologically proven cancer and, preferably, tumor positive lesions in previously performed nuclear medicine imaging examinations. The investigational drug will be given as a single administration in a dose of </= 0.1 mg BAY94-9392 (300 MBq, +/- 10%). The total duration of the study for each patient will be approximately 8 days.

    Stanford is currently not accepting patients for this trial. For more information, please contact Lindee Burton, (650) 725 - 4712.

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  • [18F]FTC-146 PET/MRI in Healthy Volunteers and in CRPS and Sciatica Recruiting

    Chronic pain can result from injured or inflamed nerves, as happens in people suffering from sciatica and CRPS. These nerve injuries or regions of nerve irritation are often the cause of pain in these conditions, but the current diagnostic tools have proven quite limited in pinpointing these areas. Several studies have implicated involvement of sigma-1 receptors in the generation and perpetuation of chronic pain conditions, while others are investigating anti sigma-1 receptor drugs for the treatment of chronic pain. Using [18F]FTC-146, a sigma-1 receptor (S1R) detector and experimental radiotracer, and positron emission tomography/magnetic resonance imaging (PET/MRI), we hope to learn the best approach to identifying the site of nerve injury/inflammation (or other tissue injury/inflammation) as they related to painful conditions, and, therefore, help identify the source of pain generation. We will characterizing the disease in patients suffering from complex regional pain syndrome (CRPS) and chronic sciatica, with the overarching goal of optimizing or developing improved pain treatment regimens. The broad objectives of this study are: - To determine the dosimetry of [18F]FTC-146 - To evaluate the safety of [18F]FTC-146 after a single administration - To evaluate the pharmacokinetics and ability of the radiotracer to reflect S1R expression in healthy subjects and specific patient subpopulations . The study is not designed to induce any physiological/pharmacological effect.

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  • A Comprehensive Study to Isolate Tumor-initiating Cells From Human Epithelial Malignancies Not Recruiting

    We hypothesize that all human malignancies harbour a subpopulation of tumor initiating cells/cancer stem cells (CSCs) that drives tumor development and potentially recurrence or metastasis of the disease. The primary aim of this study is to develop strategies for prospective isolation/enrichment of CSCs from human tumors of different tissue origins. In addition, we will characterize the signaling pathways and/or tumor specific antigens that are specific for CSCs, in order to specifically target these CSCs as the endpoint of this study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Linda Quinn, 650-723-6520.

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2016-17 Courses

Stanford Advisees

Graduate and Fellowship Programs


All Publications

  • Image-derived input function estimation on a TOF-enabled PET/MR for cerebral blood flow mapping. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Khalighi, M. M., Deller, T. W., Fan, A. P., Gulaka, P. K., Shen, B., Singh, P., Park, J. H., Chin, F. T., Zaharchuk, G. 2017: 271678X17691784


    (15)O-H2O PET imaging is an accurate method to measure cerebral blood flow (CBF) but it requires an arterial input function (AIF). Historically, image-derived AIF estimation suffers from low temporal resolution, spill-in, and spill-over problems. Here, we optimized tracer dose on a time-of-flight PET/MR according to the acquisition-specific noise-equivalent count rate curve. An optimized dose of 850 MBq of (15)O-H2O was determined, which allowed sufficient counts to reconstruct a short time-frame PET angiogram (PETA) during the arterial phase. This PETA enabled the measurement of the extent of spill-over, while an MR angiogram was used to measure the true arterial volume for AIF estimation. A segment of the high cervical arteries outside the brain was chosen, where the measured spill-in effects were minimal. CBF studies were performed twice with separate [15O]-H2O injections in 10 healthy subjects, yielding values of 88 ± 16, 44 ± 9, and 58 ± 11 mL/min/100 g for gray matter, white matter, and whole brain, with intra-subject CBF differences of 5.0 ± 4.0%, 4.1 ± 3.3%, and 4.5 ± 3.7%, respectively. A third CBF measurement after the administration of 1 g of acetazolamide showed 35 ± 23%, 29 ± 20%, and 33 ± 22% increase in gray matter, white matter, and whole brain, respectively. Based on these findings, the proposed noninvasive AIF method provides robust CBF measurement with (15)O-H2O PET.

    View details for DOI 10.1177/0271678X17691784

    View details for PubMedID 28155582

  • Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [(18)F]FTC-146. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Shen, B., Park, J. H., Hjørnevik, T., Cipriano, P. W., Yoon, D., Gulaka, P. K., Holly, D., Behera, D., Avery, B. A., Gambhir, S. S., McCurdy, C. R., Biswal, S., Chin, F. T. 2017


    Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [(18)F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [(18)F]FTC-146.[(18)F]FTC-146 is prepared via a direct [(18)F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [(18)F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects.[(18)F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/μmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [(18)F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [(18)F]FTC-146 was observed in cortical bone and muscle.A reliable and automated radiosynthesis for providing routine clinical-grade [(18)F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.

    View details for DOI 10.1007/s11307-017-1064-z

    View details for PubMedID 28280965

  • In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model SCIENTIFIC REPORTS Castellano, J. M., Palner, M., Li, S., Freeman, G. M., Andy Nguyen, A., Shen, B., Stan, T., Mosher, K. I., Chin, F. T., de Lecea, L., Luo, J., Wyss-Coray, T. 2016; 6


    The sharing of circulation between two animals using a surgical procedure known as parabiosis has created a wealth of information towards our understanding of physiology, most recently in the neuroscience arena. The systemic milieu is a complex reservoir of tissues, immune cells, and circulating molecules that is surprisingly not well understood in terms of its communication across organ systems. While the model has been used to probe complex physiological questions for many years, critical parameters of recovery and exchange kinetics remain incompletely characterized, limiting the ability to design experiments and interpret results for complex questions. Here we provide evidence that mice joined by parabiosis gradually recover much physiology relevant to the study of brain function. Specifically, we describe the timecourse for a variety of recovery parameters, including those for general health and metabolism, motor coordination, activity, and sleep behavior. Finally, we describe the kinetics of chimerism for several lymphocyte populations as well as the uptake of small molecules into the brains of mice following parabiosis. Our characterization provides an important resource to those attempting to understand the complex interplay between the immune system and the brain as well as other organ systems.

    View details for DOI 10.1038/srep29015

    View details for Web of Science ID 000378851500002

    View details for PubMedID 27364522

  • Spectrum of Ga-68-DOTA TATE Uptake in Patients With Neuroendocrine Tumors CLINICAL NUCLEAR MEDICINE Moradi, F., Jamali, M., Barkhodari, A., Schneider, B., Chin, F., Quon, A., Mittra, E. S., Iagaru, A. 2016; 41 (6): E281-E287


    To analyze the biodistribution of Ga-DOTA-TATE in the normal tissues and uptake in benign, indeterminate, and malignant lesions in a population of patients with known neuroendocrine tumors (NET) using semiquantitative standardized uptake values (SUV) measurements.One hundred four consecutively scanned patients (51 men and 53 women; mean age, 56.4 years) with confirmed diagnosis of NET underwent PET/CT 1 hour after administration of Ga-DOTA-TATE. SUVmean, and SUVmax were measured in 37 normal anatomical structures for each patient. Abnormal uptake was divided into benign, indeterminate, and malignant categories based on imaging characteristic, clinical follow-up, and pathology.High physiologic uptake (SUVmax > 7) was observed in spleen, renal parenchyma, adrenal glands, pituitary gland, stomach, and liver (in decreasing order). Moderate uptake (3.5-7) was present in the prostate, jejunum, pancreas, ileum, and salivary glands. Mild uptake (2-3.5) was present in the uterus, colon, thyroid, rectum, and skeleton. A total of 678 lesions (limited to 5 lesions with highest uptake per organ) were included in the analysis, including 127 benign and 54 indeterminate lesions. Uptake was significantly higher in malignant lesions than in benign lesions, but an overlap was noted between the groups.Ga-DOTA TATE uptake in normal and abnormal structures is highly variable in patients with NET. SUV is a useful measure for characterizing benign versus malignant lesions. Anatomical and clinical correlation may be necessary to characterize foci of intermediate uptake.

    View details for DOI 10.1097/RLU.0000000000001100

    View details for Web of Science ID 000376886800003

    View details for PubMedID 26673240

  • Pilot Comparison of Ga-68-RM2 PET and Ga-68-PSMA-11 PET in Patients with Biochemically Recurrent Prostate Cancer JOURNAL OF NUCLEAR MEDICINE Minamimoto, R., Hancock, S., Schneider, B., Chin, F. T., Jamali, M., Loening, A., Vasanawala, S., Gambhir, S. S., Iagaru, A. 2016; 57 (4): 557-562


    Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA-11) is a PET tracer that can detect prostate cancer relapses and metastases by binding to the extracellular domain of PSMA.(68)Ga-labeled DOTA-4-amino-1-carboxymethyl-piperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 ((68)Ga-RM2) is a synthetic bombesin receptor antagonist that targets gastrin-releasing peptide receptors. We present pilot data on the biodistribution of these PET tracers in a small cohort of patients with biochemically recurrent prostate cancer.Seven men (mean age ± SD, 74.3 ± 5.9 y) with biochemically recurrent prostate cancer underwent both(68)Ga-PSMA-11 PET/CT and(68)Ga-RM2 PET/MRI scans. SUVmaxand SUVmeanwere recorded for normal tissues and areas of uptake outside the expected physiologic biodistribution.All patients had a rising level of prostate-specific antigen (mean ± SD, 13.5 ± 11.5) and noncontributory results on conventional imaging.(68)Ga-PSMA-11 had the highest physiologic uptake in the salivary glands and small bowel, with hepatobiliary and renal clearance noted, whereas(68)Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake outside the expected physiologic biodistribution did not significantly differ between(68)Ga-PSMA-11 and(68)Ga-RM2; however,(68)Ga-PSMA-11 localized in a lymph node and seminal vesicle in a patient with no abnormal(68)Ga-RM2 uptake. Abdominal periaortic lymph nodes were more easily visualized by(68)Ga-RM2 in two patients because of lack of interference by radioactivity in the small intestine.(68)Ga-PSMA-11 and(68)Ga-RM2 had distinct biodistributions in this small cohort of patients with biochemically recurrent prostate cancer. Additional work is needed to understand the expression of PSMA and gastrin-releasing peptide receptors in different types of prostate cancer.

    View details for DOI 10.2967/jnumed.115.168393

    View details for Web of Science ID 000373627800022

    View details for PubMedID 26659347

  • Pilot Preclinical and Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for PET/CT Imaging of Intracranial Malignancies. PloS one Mittra, E. S., Koglin, N., Mosci, C., Kumar, M., Hoehne, A., Keu, K. V., Iagaru, A. H., Mueller, A., Berndt, M., Bullich, S., Friebe, M., Schmitt-Willich, H., Gekeler, V., Fels, L. M., Bacher-Stier, C., Moon, D. H., Chin, F. T., Stephens, A. W., Dinkelborg, L. M., Gambhir, S. S. 2016; 11 (2)


    (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is a novel radiopharmaceutical for Positron Emission Tomography (PET) imaging. It is a glutamate analogue that can be used to measure xC- transporter activity. This study was performed to assess the feasibility of 18F-FSPG for imaging orthotopic brain tumors in small animals and the translation of this approach in human subjects with intracranial malignancies.For the small animal study, GS9L glioblastoma cells were implanted into brains of Fischer rats and studied with 18F-FSPG, the 18F-labeled glucose derivative 18F-FDG and with the 18F-labeled amino acid derivative 18F-FET. For the human study, five subjects with either primary or metastatic brain cancer were recruited (mean age 50.4 years). After injection of 300 MBq of 18F-FSPG, 3 whole-body PET/Computed Tomography (CT) scans were obtained and safety parameters were measured. The three subjects with brain metastases also had an 18F-FDG PET/CT scan. Quantitative and qualitative comparison of the scans was performed to assess kinetics, biodistribution, and relative efficacy of the tracers.In the small animals, the orthotopic brain tumors were visualized well with 18F-FSPG. The high tumor uptake of 18F-FSPG in the GS9L model and the absence of background signal led to good tumor visualization with high contrast (tumor/brain ratio: 32.7). 18F-FDG and 18F-FET showed T/B ratios of 1.7 and 2.8, respectively. In the human pilot study, 18F-FSPG was well tolerated and there was similar distribution in all patients. All malignant lesions were positive with 18F-FSPG except for one low-grade primary brain tumor. In the 18F-FSPG-PET-positive tumors a similar T/B ratio was observed as in the animal model.18F-FSPG is a novel PET radiopharmaceutical that demonstrates good uptake in both small animal and human studies of intracranial malignancies. Future studies on larger numbers of subjects and a wider array of brain tumors are NCT01186601.

    View details for DOI 10.1371/journal.pone.0148628

    View details for PubMedID 26890637

  • Efficient automated syntheses of high specific activity 6-[F-18]fluorodopamine using a diaryliodonium salt precursor JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Neumann, K. D., Qin, L., Vavere, A. L., Shen, B., Miao, Z., Chin, F. T., Shulkin, B. L., Snyder, S. E., DiMagno, S. G. 2016; 59 (1): 30-34


    6-[(18)F]Fluorodopamine (6-[(18) F]F-DA) is a positron emission tomography radiopharmaceutical used to image sympathetic cardiac innervation and neuroendocrine tumors. Imaging with 6-[(18)F]F-DA is constrained, in part, by the bioactivity and neurotoxicity of 6-[(19)F]fluorodopamine. Furthermore, routine access to this radiotracer is limited by the inherent difficulty of incorporation of [(18)F]fluoride into electron-rich aromatic substrates. We describe the simple and direct preparation of high specific activity (SA) 6-[(18)F]F-DA from no-carrier-added (n.c.a.) [(18)F]fluoride. Incorporation of n.c.a. [(18)F]fluoride into a diaryliodonium salt precursor was achieved in 50-75% radiochemical yields (decay corrected to end of bombardment). Synthesis of 6-[(18)F]F-DA on the IBA Synthera® and GE TRACERlab FX-FN automated platforms gave 6-[(18)F]F-DA in >99% chemical and radiochemical purities after HPLC purification. The final non-corrected yields of 6-[(18)F]F-DA were 25 ± 4% (n = 4, 65 min) and 31 ± 6% (n = 3, 75 min) using the Synthera and TRACERlab modules, respectively. Efficient access to high SA 6-[(18)F]F-DA from a diaryliodonium salt precursor and n.c.a. [(18)F]fluoride is provided by a relatively subtle change in reaction conditions - replacement of a polar aprotic solvent (acetonitrile) with a relatively nonpolar solvent (toluene) during the critical radiofluorination reaction. Implementation of this process on common radiochemistry platforms should make 6-[(18)F]F-DA readily available to the wider imaging community.

    View details for DOI 10.1002/jlcr.3367

    View details for Web of Science ID 000368945200005

    View details for PubMedID 26695865

  • Quantification of Highly Selective Sigma-1 Receptor Antagonist CM304 using Liquid Chromatography Tandem Mass Spectrometry and its application to a Pre-clinical Pharmacokinetic Study. Drug testing and analysis Avery, B. A., Vuppala, P. K., Jamalapuram, S., Sharma, A., Mesangeau, C., Chin, F. T., McCurdy, C. R. 2016


    An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for quantification CM304, a novel and highly selective sigma-1 receptor antagonist that has recently entered into human clinical trials. A structural analogue of CM304, SN56, was used as the internal standard (IS). Chromatographic separation was achieved on an Acquity UPLC(TM) BEH C18 (1.7 µm, 2.1 mm × 50 mm) column using a mobile phase [water : methanol (0.1 %v/v formic acid; 50 : 50, %v/v)] at a flow rate of 0.2 mL/min. Mass spectrometric detection was performed in the positive ionization mode with multiple reaction monitoring (MRM) using m/z transitions of 337 > 238 for CM304 and 319 > 220 for the IS. The method was found to be linear and reproducible with a regression coefficient consistently > 0.99 for the calibration range of 3 to 3000 ng/mL. The extraction recovery ranged from 91.5 to 98.4% from spiked (7.5, 300 and 2526 ng/mL) plasma quality control samples. The precision (%RSD; 1.1 to 2.9%) and accuracy (%RE; -1.9 to 1.8%) were within acceptable limit. The validated method was successfully applied to a single dose oral and intravenous (I.V.) pharmacokinetic study of CM304 in rats. Following I.V. administration, the compound exhibited adequate exposure along with high extravascular distribution and insignificant amount of extra hepatic metabolism.

    View details for DOI 10.1002/dta.2156

    View details for PubMedID 28039926

  • Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys. Neurobiology of stress Lee, A. G., Nechvatal, J. M., Shen, B., Buckmaster, C. L., Levy, M. J., Chin, F. T., Schatzberg, A. F., Lyons, D. M. 2016; 3: 68–73


    Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3) in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [(11)C]raclopride binding using positron emission tomography (PET). DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no-stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys.

    View details for DOI 10.1016/j.ynstr.2016.02.001

    View details for PubMedID 27981179

  • Effects of common anesthetic agents on [(18)F]flumazenil binding to the GABAA receptor. EJNMMI research Palner, M., Beinat, C., Banister, S., Zanderigo, F., Park, J. H., Shen, B., Hjoernevik, T., Jung, J. H., Lee, B. C., Kim, S. E., Fung, L., Chin, F. T. 2016; 6 (1): 80


    The availability of GABAA receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [(18)F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [(18)F]flumazenil to GABAA receptors in mice.Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [(18)F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [(18)F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (VT*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.PET images showed persistence of high [(18)F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state VT* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.Anesthesia has pronounced effects on the binding and blood-brain distribution of [(18)F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABAA receptors involving the use of anesthesia.

    View details for DOI 10.1186/s13550-016-0235-2

    View details for PubMedID 27826950

  • [C-11]Ascorbic and [C-11]dehydroascorbic acid, an endogenous redox pair for sensing reactive oxygen species using positron emission tomography CHEMICAL COMMUNICATIONS Carroll, V. N., Truillet, C., Shen, B., Flavell, R. R., Shao, X., Evans, M. J., VanBrocklin, H. F., Scott, P. J., Chin, F. T., Wilson, D. M. 2016; 52 (27): 4888-4890

    View details for DOI 10.1039/c6cc00895j

    View details for Web of Science ID 000373061300008

  • Biodistribution of the F-18-FPPRGD(2) PET radiopharmaceutical in cancer patients: an atlas of SUV measurements EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Minamimoto, R., Jamali, M., Barkhodari, A., Mosci, C., Mittra, E., Shen, B., Chin, F., Gambhir, S. S., Iagaru, A. 2015; 42 (12): 1850-1858


    The aim of this study was to investigate the biodistribution of 2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) ((18)F-FPPRGD2) in cancer patients and to compare its uptake in malignant lesions with (18)F-FDG uptake.A total of 35 patients (11 men, 24 women, mean age 52.1 ± 10.8 years) were enrolled prospectively and had (18)F-FPPRGD2 PET/CT prior to treatment. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 23 normal tissues in each patient, as well as in known or suspected cancer lesions. Differences between (18)F-FPPRGD2 uptake and (18)F-FDG uptake were also evaluated in 28 of the 35 patients.Areas of high (18)F-FPPRGD2 accumulation (SUVmax range 8.9 - 94.4, SUVmean range 7.1 - 64.4) included the bladder and kidneys. Moderate uptake (SUVmax range 2.1 - 6.3, SUVmean range 1.1 - 4.5) was found in the choroid plexus, salivary glands, thyroid, liver, spleen, pancreas, small bowel and skeleton. Compared with (18)F-FDG, (18)F-FPPRGD2 showed higher tumor-to-background ratio in brain lesions (13.4 ± 8.5 vs. 1.1 ± 0.5, P < 0.001), but no significant difference in body lesions (3.2 ± 1.9 vs. 4.4 ± 4.2, P = 0.10). There was no significant correlation between the uptake values (SUVmax and SUVmean) for (18)F FPPRGD2 and those for (18)F-FDG.The biodistribution of (18)F-FPPRGD2 in cancer patients is similar to that of other RGD dimer peptides and it is suitable for clinical use. The lack of significant correlation between (18)F-FPPRGD2 and (18)F-FDG uptake confirms that the information provided by each PET tracer is different.

    View details for DOI 10.1007/s00259-015-3096-4

    View details for Web of Science ID 000361997600010

  • PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2 SCIENCE TRANSLATIONAL MEDICINE Witney, T. H., James, M. L., Shen, B., Chang, E., Pohling, C., Arksey, N., Hoehne, A., Shuhendler, A., Park, J., Bodapati, D., Weber, J., Gowrishankar, G., Rao, J., Chin, F. T., Gambhir, S. S. 2015; 7 (310)
  • Bright Lu2O3:Eu Thin-Film Scintillators for High-Resolution Radioluminescence Microscopy ADVANCED HEALTHCARE MATERIALS Sengupta, D., Miller, S., Marton, Z., Chin, F., Nagarkar, V., Pratx, G. 2015; 4 (14): 2064-2070
  • F-18-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models PLOS ONE Ali, R., Apte, S., Vilalta, M., Subbarayan, M., Miao, Z., Chin, F. T., Graves, E. E. 2015; 10 (10)
  • Further validation to support clinical translation of [F-18]FTC-146 for imaging sigma-1 receptors EJNMMI RESEARCH Shen, B., James, M. L., Andrews, L., Lau, C., Chen, S., Palner, M., Miao, Z., Arksey, N. C., Shuhendler, A. J., Scatliffe, S., Kaneshige, K., Parsons, S. M., McCurdy, C. R., Salehi, A., Gambhir, S. S., Chin, F. T. 2015; 5
  • A Systematic Comparison of F-18-C-SNAT to Established Radiotracer Imaging Agents for the Detection of Tumor Response to Treatment CLINICAL CANCER RESEARCH Witney, T. H., Hoehne, A., Reeves, R. E., Ilovich, O., Namavari, M., Shen, B., Chin, F. T., Rao, J., Gambhir, S. S. 2015; 21 (17): 3896-3905


    An early readout of tumor response to therapy through measurement of drug or radiation-induced cell death may provide important prognostic indications and improved patient management. It has been shown that the uptake of (18)F-C-SNAT can be used to detect early response to therapy in tumors by positron emission tomography (PET) via a mechanism of caspase-3-triggered nanoaggregation.Here, we compared the preclinical utility of (18)F-C-SNAT for the detection of drug-induced cell death to clinically evaluated radiotracers, (18)F-FDG, (99m)Tc-Annexin V, and (18)F-ML-10 in tumor cells in culture, and in tumor-bearing mice in vivo.In drug-treated lymphoma cells, (18)F-FDG, (99m)Tc-Annexin V, and (18)F-C-SNAT cell-associated radioactivity correlated well to levels of cell death (R(2) > 0.8; P < 0.001), with no correlation measured for (18)F-ML-10 (R(2) = 0.05; P > 0.05). A similar pattern of response was observed in two human NSCLC cell lines following carboplatin treatment. EL-4 tumor uptake of (99m)Tc-Annexin V and (18)F-C-SNAT were increased 1.4- and 2.1-fold, respectively, in drug-treated versus naïve control animals (P < 0.05), although (99m)Tc-Annexin V binding did not correlate to ex vivo TUNEL staining of tissue sections. A differential response was not observed with either (18)F-FDG or (18)F-ML-10.We have demonstrated here that (18)F-C-SNAT can sensitively detect drug-induced cell death in murine lymphoma and human NSCLC. Despite favorable image contrast obtained with (18)F-C-SNAT, the development of next-generation derivatives, using the same novel and promising uptake mechanism, but displaying improved biodistribution profiles, are warranted for maximum clinical utility. Clin Cancer Res; 21(17); 3896-905. ©2015 AACR.

    View details for DOI 10.1158/1078-0432.CCR-14-3176

    View details for Web of Science ID 000361910000013

    View details for PubMedID 25972517

  • Preclinical Kinetic Analysis of the Caspase-3/7 PET Tracer F-18-C-SNAT: Quantifying the Changes in Blood Flow and Tumor Retention After Chemotherapy JOURNAL OF NUCLEAR MEDICINE Palner, M., Shen, B., Jeon, J., Lin, J., Chin, F. T., Rao, J. 2015; 56 (9): 1415-1421


    Early detection of tumor response to therapy is crucial to the timely identification of the most efficacious treatments. We recently developed a novel apoptosis imaging tracer, (18)F-C-SNAT (C-SNAT is caspase-sensitive nanoaggregation tracer), that undergoes an intramolecular cyclization reaction after cleavage by caspase-3/7, a biomarker of apoptosis. This caspase-3/7-dependent reaction leads to an enhanced accumulation and retention of (18)F activity in apoptotic tumors. This study aimed to fully examine in vivo pharmacokinetics of the tracer through PET imaging and kinetic modeling in a preclinical mouse model of tumor response to systemic anticancer chemotherapy.Tumor-bearing nude mice were treated 3 times with intravenous injections of doxorubicin before undergoing a 120-min dynamic (18)F-C-SNAT PET/CT scan. Time-activity curves were extracted from the tumor and selected organs. A 2-tissue-compartment model was fitted to the time-activity curves from tumor and muscle, using the left ventricle of the heart as input function, and the pharmacokinetic rate constants were calculated.Both tumor uptake (percentage injected dose per gram) and the tumor-to-muscle activity ratio were significantly higher in the treated mice than untreated mice. Pharmacokinetic rate constants calculated by the 2-tissue-compartment model showed a significant increase in delivery and accumulation of the tracer after the systemic chemotherapeutic treatment. Delivery of (18)F-C-SNAT to the tumor tissue, quantified as K1, increased from 0.31 g⋅(mL⋅min)(-1) in untreated mice to 1.03 g⋅(mL⋅min)(-1) in treated mice, a measurement closely related to changes in blood flow. Accumulation of (18)F-C-SNAT, quantified as k3, increased from 0.03 to 0.12 min(-1), proving a higher retention of (18)F-C-SNAT in treated tumors independent from changes in blood flow. An increase in delivery was also found in the muscular tissue of treated mice without increasing accumulation.(18)F-C-SNAT has significantly increased tumor uptake and significantly increased tumor-to-muscle ratio in a preclinical mouse model of tumor therapy. Furthermore, our kinetic modeling of (18)F-C-SNAT shows that chemotherapeutic treatment increased accumulation (k3) in the treated tumors, independent of increased delivery (K1).

    View details for DOI 10.2967/jnumed.115.155259

    View details for Web of Science ID 000361153000029

  • Single-Cell Analysis of [18F]Fluorodeoxyglucose Uptake by Droplet Radiofluidics ANALYTICAL CHEMISTRY Tuerkcan, S., Julia Nguyen, J., Vilalta, M., Shen, B., Chin, F. T., Pratx, G., Abbyad, P. 2015; 87 (13): 6667-6673


    Radiolabels can be used to detect small biomolecules with high sensitivity and specificity without interfering with the biochemical activity of the labeled molecule. For instance, the radiolabeled glucose analogue, [18F]fluorodeoxyglucose (FDG), is routinely used in positron emission tomography (PET) scans for cancer diagnosis, staging, and monitoring. However, despite their widespread usage, conventional radionuclide techniques are unable to measure the variability and modulation of FDG uptake in single cells. We present here a novel microfluidic technique, dubbed droplet radiofluidics, that can measure radiotracer uptake for single cells encapsulated into an array of microdroplets. The advantages of this approach are multiple. First, droplets can be quickly and easily positioned in a predetermined pattern for optimal imaging throughput. Second, droplet encapsulation reduces cell efflux as a confounding factor, because any effluxed radionuclide is trapped in the droplet. Last, multiplexed measurements can be performed using fluorescent labels. In this new approach, intracellular radiotracers are imaged on a conventional fluorescence microscope by capturing individual flashes of visible light that are produced as individual positrons, emitted during radioactive decay, traverse a scintillator plate placed below the cells. This method is used to measure the cell-to-cell heterogeneity in the uptake of tracers such as FDG in cell lines and cultured primary cells. The capacity of the platform to perform multiplexed measurements was demonstrated by measuring differential FDG uptake in single cells subjected to different incubation conditions and expressing different types of glucose transporters. This method opens many new avenues of research in basic cell biology and human disease by capturing the full range of stochastic variations in highly heterogeneous cell populations in a repeatable and high-throughput manner.

    View details for DOI 10.1021/acs.analchem.5b00792

    View details for Web of Science ID 000357839700038

  • Validation of Cu-64-DOTA-Rituximab Injection Preparation Under Good Manufacturing Practices: A PET Tracer for Imaging of B-Cell Non-Hodgkin Lymphoma MOLECULAR IMAGING Natarajan, A., Arksey, N., Iagaru, A., Chin, F. T., Gambhir, S. S. 2015; 14
  • Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO) EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Banister, S. D., Beinat, C., Wilkinson, S. M., Shen, B., Bartoli, C., Selleri, S., Da Pozzo, E., Martini, C., Chin, F. T., Kassiou, M. 2015; 93: 392-400


    Sixteen new phenyl alkyl ether derivatives (12, 14-28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [(3)H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134-331% above baseline) in a rat C6 glioma cell steroidogenesis assay.

    View details for DOI 10.1016/j.ejmech.2015.02.004

    View details for Web of Science ID 000351646100040

  • PET Imaging of Translocator Protein (18 kDa) in a Mouse Model of Alzheimer's Disease Using N-(2,5-Dimethoxybenzyl)-2-F-18-Fluoro-N-(2-Phenoxyphenyl)Acetamide JOURNAL OF NUCLEAR MEDICINE James, M. L., Belichenko, N. P., Nguyen, T. V., Andrews, L. E., Ding, Z., Liu, H., Bodapati, D., Arksey, N., Shen, B., Cheng, Z., Wyss-Coray, T., Gambhir, S. S., Longo, F. M., Chin, F. T. 2015; 56 (2): 311-316


    Herein we aimed to evaluate the utility of N-(2,5-dimethoxybenzyl)-2-(18)F-fluoro-N-(2-phenoxyphenyl)acetamide ((18)F-PBR06) for detecting alterations in translocator protein (TSPO) (18 kDa), a biomarker of microglial activation, in a mouse model of Alzheimer's disease (AD).Wild-type (wt) and AD mice (i.e., APP(L/S)) underwent (18)F-PBR06 PET imaging at predetermined time points between the ages of 5-6 and 15-16 mo. MR images were fused with PET/CT data to quantify (18)F-PBR06 uptake in the hippocampus and cortex. Ex vivo autoradiography and TSPO/CD68 immunostaining were also performed using brain tissue from these mice.PET images showed significantly higher accumulation of (18)F-PBR06 in the cortex and hippocampus of 15- to 16-mo-old APP(L/S) mice than age-matched wts (cortex/muscle: 2.43 ± 0.19 vs. 1.55 ± 0.15, P < 0.005; hippocampus/muscle: 2.41 ± 0.13 vs. 1.55 ± 0.12, P < 0.005). And although no significant difference was found between wt and APP(L/S) mice aged 9-10 mo or less using PET (P = 0.64), we were able to visualize and quantify a significant difference in (18)F-PBR06 uptake in these mice using autoradiography (cortex/striatum: 1.13 ± 0.04 vs. 0.96 ± 0.01, P < 0.05; hippocampus/striatum: 1.266 ± 0.003 vs. 1.096 ± 0.017, P < 0.001). PET results for 15- to 16-mo-old mice correlated well with autoradiography and immunostaining (i.e., increased (18)F-PBR06 uptake in brain regions containing elevated CD68 and TSPO staining in APP(L/S) mice, compared with wts).(18)F-PBR06 shows great potential as a tool for visualizing TSPO/microglia in the progression and treatment of AD.

    View details for DOI 10.2967/jnumed.114.141648

    View details for Web of Science ID 000349324300035

    View details for PubMedID 25613536

  • Validation of 64Cu-DOTA-rituximab injection preparation under good manufacturing practices: a PET tracer for imaging of B-cell non-Hodgkin lymphoma. Molecular imaging Natarajan, A., Arksey, N., Iagaru, A., Chin, F. T., Gambhir, S. S. 2015; 14


    AbstractManufacturing of 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-rituximab injection under good manufacturing practices (GMP) was validated for imaging of patients with CD20+ B-cell non-Hodgkin lymphoma. Rituximab was purified by size exclusion high performance liquid chromatography (HPLC) and conjugated to DOTA-mono-(N-hydroxysuccinimidyl) ester. 64CuCl2, buffers, reagents, and other raw materials were obtained as high-grade quality. Following a semi-automated synthesis of 64Cu-DOTA-rituximab, a series of quality control tests was performed. The product was further tested in vivo using micro-positron emission tomography/computed tomography (PET/CT) to assess targeting ability towards human CD20 in transgenic mice. Three batches of 64Cu-DOTA-rituximab final product were prepared as per GMP specifications. The radiolabeling yield from these batches was 93.1 ± 5.8%; these provided final product with radiopharmaceutical yield, purity, and specific activity of 59.2 ± 5.1% (0.9 ± 0.1 GBq of 64Cu), > 95% (by HPLC and radio-thin layer chromatography), and 229.4 ± 43.3 GBq/µmol (or 1.5 ± 0.3 MBq/µg), respectively. The doses passed apyrogenicity and human serum stability specifications, were sterile up to 14 days, and retained > 60% immunoreactivity. In vivo micro-PET/CT mouse images at 24 hours postinjection showed that the tracer targeted the intended sites of human CD20 expression. Thus, we have validated the manufacturing of GMP grade 64Cu-DOTA-rituximab for injection in the clinical setting.

    View details for DOI 10.2310/7290.2014.00055

    View details for PubMedID 25762106

  • 18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models. PloS one Ali, R., Apte, S., Vilalta, M., Subbarayan, M., Miao, Z., Chin, F. T., Graves, E. E. 2015; 10 (10)


    We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.

    View details for DOI 10.1371/journal.pone.0139425

    View details for PubMedID 26431331

  • The Relationship Between Serial [(18) F]PBR06 PET Imaging of Microglial Activation and Motor Function Following Stroke in Mice MOLECULAR IMAGING AND BIOLOGY Lartey, F. M., Ahn, G., Ali, R., Rosenblum, S., Miao, Z., Arksey, N., Shen, B., Colomer, M. V., Rafat, M., Liu, H., Alejandre-Alcazar, M. A., Chen, J. W., Palmer, T., Chin, F. T., Guzman, R., Loo, B. W., Graves, E. 2014; 16 (6): 821-829
  • A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging MOLECULAR PHARMACEUTICS Jiang, L., Kimura, R. H., Ma, X., Tu, Y., Miao, Z., Shen, B., Chin, F. T., Shi, H., Gambhir, S. S., Cheng, Z. 2014; 11 (11): 3885-3892

    View details for DOI 10.1021/mp500018s

    View details for Web of Science ID 000344307700012

  • F-18-FPPRGD2 PET/CT: Pilot Phase Evaluation of Breast Cancer Patients RADIOLOGY Lagaru, A., Mosci, C., Shen, B., Chin, F. T., Mittra, E., Telli, M. L., Gambhir, S. S. 2014; 273 (2): 549-559
  • Comparison of Two Site-Specifically F-18-Labeled Affibodies for PET Imaging of EGFR Positive Tumors MOLECULAR PHARMACEUTICS Su, X., Cheng, K., Jeon, J., Shen, B., Venturin, G. T., Hu, X., Rao, J., Chin, F. T., Wu, H., Cheng, Z. 2014; 11 (11): 3947-3956

    View details for DOI 10.1021/mp5003043

    View details for Web of Science ID 000344307700019

  • Fully Automated Production of Diverse 18F-Labeled PET Tracers on the ELIXYS Multireactor Radiosynthesizer Without Hardware Modification. Journal of nuclear medicine technology Lazari, M., Collins, J., Shen, B., Farhoud, M., Yeh, D., Maraglia, B., Chin, F. T., Nathanson, D. A., Moore, M., van Dam, R. M. 2014; 42 (3): 203-210


    Fully automated radiosynthesizers are continuing to be developed to meet the growing need for the reliable production of PET tracers made under current good manufacturing practice guidelines. There is a current trend toward supporting kitlike disposable cassettes that come preconfigured for particular tracers, thus eliminating the need for cleaning protocols between syntheses and enabling quick transitions to synthesizing other tracers. Though ideal for production, these systems are often limited for the development of novel tracers because of pressure, temperature, and chemical compatibility considerations. This study demonstrated the versatile use of the ELIXYS fully automated radiosynthesizer to adapt and produce 8 different (18)F-labeled PET tracers of varying complexity.Three-reactor syntheses of 2-deoxy-2-(18)F-fluoro-β-d-arabinofuranosylcytosine (d-(18)F-FAC), 2-deoxy-2-(18)F-fluoro-5-methyl-β-l-arabinofuranosyluracil (l-(18)F-FMAU), and 2-deoxy-2-(18)F-fluoro-5-ethyl-β-d-arabinofuranosyluracil (d-(18)F-FEAU) along with the 1-reactor syntheses of d-(18)F-FEAU, (18)F-FDG, 3-deoxy-3-(18)F-fluoro-l-thymidine ((18)F-FLT), (18)F-fallypride, 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)-guanine ((18)F-FHBG), and N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB), were all produced using ELIXYS without the need for any hardware modifications or reconfiguration. Synthesis protocols were adapted and slightly modified from those in the literature but were not fully optimized. Furthermore, (18)F-FLT, (18)F-FDG, and (18)F-fallypride were produced sequentially on the same day and used for preclinical imaging of A431 tumor-bearing severe combined immunodeficient mice and wild-type BALB/c mice. To assess future translation to the clinical setting, several batches of tracers were subjected to a full set of quality control tests.All tracers were produced with radiochemical yields comparable to those in the literature. (18)F-FLT, (18)F-FDG, and (18)F-fallypride were successfully used to image the mice, with results consistent with those reported in the literature. All tracers that were subjected to clinical quality control tests passed.The ELIXYS radiosynthesizer facilitates rapid tracer development and is capable of producing multiple (18)F-labeled PET tracers suitable for clinical applications using the same hardware setup.

    View details for DOI 10.2967/jnmt.114.140392

    View details for PubMedID 25033883

  • Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors NUCLEAR MEDICINE AND BIOLOGY Lodge, N. J., Li, Y., Chin, F. T., Dischino, D. D., Zoghbi, S. S., Deskus, J. A., Mattson, R. J., Imaizumi, M., Pieschl, R., Molski, T. F., Fujita, M., Dulac, H., Zaczek, R., Bronson, J. J., Macor, J. E., Innis, R. B., Pike, V. W. 2014; 41 (6): 524-535


    A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold.CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [(125)I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [(3)H]BMS-728300.The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [(3)H]BMS-728300 and the two (18)F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [(18)F]BMS-721313, [(18)F]BMS-732098 and [(11)C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro.Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.

    View details for DOI 10.1016/j.nucmedbio.2014.03.005

    View details for Web of Science ID 000336946400013

    View details for PubMedID 24793011

  • PET Imaging of Stroke-Induced Neuroinflammation in Mice Using [F-18]PBR06 MOLECULAR IMAGING AND BIOLOGY Lartey, F. M., Ahn, G., Shen, B., Cord, K., Smith, T., Chua, J. Y., Rosenblum, S., Liu, H., James, M. L., Chernikova, S., Lee, S. W., Pisani, L. J., Tirouvanziam, R., Chen, J. W., Palmer, T. D., Chin, F. T., Guzman, R., Graves, E. E., Loo, B. W. 2014; 16 (1): 109-117


    The purpose of this study is to evaluate the 18 kDa translocator protein (TSPO) radioligand [(18)F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([(18)F]PBR06) as a positron emission tomography (PET) imaging biomarker of stroke-induced neuroinflammation in a rodent model.Stroke was induced by transient middle cerebral artery occlusion in Balb/c mice. Dynamic PET/CT imaging with displacement and preblocking using PK111195 was performed 3 days later. PET data were correlated with immunohistochemistry (IHC) for the activated microglial markers TSPO and CD68 and with autoradiography.[(18)F]PBR06 accumulation peaked within the first 5 min postinjection, then decreased gradually, remaining significantly higher in infarct compared to noninfarct regions. Displacement or preblocking with PK11195 eliminated the difference in [(18)F]PBR06 uptake between infarct and noninfarct regions. Autoradiography and IHC correlated well spatially with uptake on PET.[(18)F]PBR06 PET specifically images TSPO in microglial neuroinflammation in a mouse model of stroke and shows promise for imaging and monitoring microglial activation/neuroinflammation in other disease models.

    View details for DOI 10.1007/s11307-013-0664-5

    View details for Web of Science ID 000329793200014

    View details for PubMedID 23836504

  • Evaluation of s-1 Receptor Radioligand 18F-FTC-146 in Rats and Squirrel Monkeys Using PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Shen, B., Nielsen, C. H., Behera, D., Buckmaster, C. L., Mesangeau, C., Zavaleta, C., Vuppala, P. K., Jamalapuram, S., Avery, B. A., Lyons, D. M., McCurdy, C. R., Biswal, S., Gambhir, S. S., Chin, F. T. 2014; 55 (1): 147-153


    The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

    View details for DOI 10.2967/jnumed.113.120261

    View details for PubMedID 24337599

  • A F-18-Labeled Saxitoxin Derivative for in Vivo PET-MR Imaging of Voltage-Gated Sodium Channel Expression Following Nerve Injury JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hoehne, A., Behera, D., Parsons, W. H., James, M. L., Shen, B., Borgohain, P., Bodapati, D., Prabhakar, A., Gambhir, S. S., Yeomans, D. C., Biswal, S., Chin, F. T., Du Bois, J. 2013; 135 (48): 18012-18015


    Both chronic and neuropathic pain conditions are associated with increased expression of certain voltage-gated sodium ion channel (NaV) isoforms in peripheral sensory neurons. A method for noninvasive imaging of these channels could represent a powerful tool for investigating aberrant expression of NaV and its role in pain pathogenesis. Herein, we describe the synthesis and evaluation of a positron emission tomography (PET) radiotracer targeting NaVs, the design of which is based on the potent, NaV-selective inhibitor saxitoxin. Both autoradiography analysis of sciatic nerves excised from injured rats as well as whole animal PET-MR imaging demonstrate that a systemically administered [(18)F]-labeled saxitoxin derivative concentrates at the site of nerve injury, consistent with upregulated sodium channel expression following axotomy. This type of PET agent has potential use for serial monitoring of channel expression levels at injured nerves throughout wound healing and/or following drug treatment. Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation.

    View details for DOI 10.1021/ja408300e

    View details for Web of Science ID 000328100000002

  • Integrin-Targeted Molecular Imaging of Experimental Abdominal Aortic Aneurysms by 18F-labeled Arg-Gly-Asp Positron-Emission Tomography. Circulation. Cardiovascular imaging Kitagawa, T., Kosuge, H., Chang, E., James, M. L., Yamamoto, T., Shen, B., Chin, F. T., Gambhir, S. S., Dalman, R. L., McConnell, M. V. 2013; 6 (6): 950-956


    Background- Both inflammation and neoangiogenesis contribute to abdominal aortic aneurysm (AAA) disease. Arg-Gly-Asp-based molecular imaging has been shown to detect the integrin αvβ3. We studied a clinical dimeric (18)F-labeled Arg-Gly-Asp positron-emission tomography (PET) agent ((18)F-FPPRGD2) for molecular imaging of experimental AAAs. Methods and Results- Murine AAAs were induced in Apo-E-deficient mice by angiotensin II infusion, with monitoring of aortic diameter on ultrasound. AAA (n=10) and saline-infused control mice (n=7) were injected intravenously with (18)F-FPPRGD2, as well as an intravascular computed tomography contrast agent, then scanned using a small-animal PET/computed tomography scanner. Aortic uptake of (18)F-FPPRGD2 was quantified by percentage-injected dose per gram and target-to-=0.003; median target-to-=0.0008). Ex vivo autoradiography demonstrated high uptake of (18)F-FPPRGD2 into the AAA wall, with immunohistochemistry showing substantial cluster of differentiation (CD)-11b(+) macrophages and CD-31(+) neovessels. Target-to-=-0.29, P=0.41) but did strongly correlate with both mural macrophage density (r=0.79, P=0.007) and neovessel counts (r=0.87, P=0.001) on immunohistochemistry. Conclusions- PET imaging of experimental AAAs using (18)F-FPPRGD2 detects biologically active disease, correlating to the degree of vascular inflammation and neoangiogenesis. This may provide a clinically translatable molecular imaging approach to characterize AAA biology to predict risk beyond size alone.

    View details for DOI 10.1161/CIRCIMAGING.113.000234

    View details for PubMedID 23995363

  • Positron Emission Tomography Imaging of Drug-Induced Tumor Apoptosis with a Caspase-Triggered Nanoaggregation Probe ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Shen, B., Jeon, J., Palner, M., Ye, D., Shuhendler, A., Chin, F. T., Rao, J. 2013; 52 (40): 10511-10514


    Drug Design: An (18) F-labeled caspase-3-sensitive nanoaggregation positron emission tomography tracer was prepared and evaluated for imaging the caspase-3 activity in doxorubicin-treated tumor xenografts. Enhanced retention of the (18) F activity in apoptotic tumors is achieved through intramolecular macrocyclization and in situ aggregation upon caspase-3 activation.

    View details for DOI 10.1002/anie.201303422

    View details for Web of Science ID 000325091500023

  • 18F-fluorobenzoate-labeled cystine knot peptides for PET imaging of integrin avß6. Journal of nuclear medicine Hackel, B. J., Kimura, R. H., Miao, Z., Liu, H., Sathirachinda, A., Cheng, Z., Chin, F. T., Gambhir, S. S. 2013; 54 (7): 1101-1105


    Integrin αvβ6 is a cell surface receptor minimally expressed by healthy tissue but elevated in lung, colon, skin, ovarian, cervical, and pancreatic cancers. A molecular PET agent for integrin αvβ6 could provide significant clinical utility by facilitating both cancer staging and treatment monitoring to more rapidly identify an effective therapeutic approach. METHODS: Here, we evaluated 2 cystine knot peptides, R01 and S02, previously engineered with a 3-6 nM affinity for integrin αvβ6, for (18)F radiolabeling and PET imaging of BxPC3 pancreatic adenocarcinoma xenografts in mice. Cystine knot peptides were labeled with N-succinimidyl-4-(18)F-fluorobenzoate and evaluated for binding affinity and serum stability. Peptides conjugated with (18)F-fluorobenzoate (2-3 MBq) were injected via the tail vein into nude mice xenografted with BxPC3 (integrin αvβ6-positive) or 293 (integrin αvβ6-negative) tumors. Small-animal PET scans were acquired at 0.5, 1, and 2 h after injection. Ex vivo γ-counting of dissected tissues was performed at 0.5 and 2 h. RESULTS: (18)F-fluorobenzoate peptides were produced in 93% ((18)F-fluorobenzoate-R01) and 99% ((18)F-fluorobenzoate-S02) purity. (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02 had affinities of 1.1 ± 0.2 and 0.7 ± 0.4 nM, respectively, and were 87% and 94%, respectively, stable in human serum at 37°C for 2 h. (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02 exhibited 2.3 ± 0.6 and 1.3 ± 0.4 percentage injected dose per gram (%ID/g), respectively, in BxPC3 xenografted tumors at 0.5 h (n = 4-5). Target specificity was confirmed by low tumor uptake in integrin αvβ6-negative 293 tumors (1.4 ± 0.6 and 0.5 ± 0.2 %ID/g, respectively, for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02; both P < 0.05; n = 3-4) and low muscle uptake (3.1 ± 1.0 and 2.7 ± 0.4 tumor to muscle for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02, respectively). Small-animal PET data were corroborated by ex vivo γ-counting of dissected tissues, which demonstrated low uptake in nontarget tissues with only modest kidney uptake (9.2 ± 3.3 and 1.9 ± 1.2 %ID/g, respectively, at 2 h for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02; n = 8). Uptake in healthy pancreas was low (0.3% ± 0.1% for (18)F-fluorobenzoate-R01 and 0.03% ± 0.01% for (18)F-fluorobenzoate-S02; n = 8). CONCLUSION: These cystine knot peptide tracers, in particular (18)F-fluorobenzoate-R01, show translational promise for molecular imaging of integrin αvβ6 overexpression in pancreatic and other cancers.

    View details for DOI 10.2967/jnumed.112.110759

    View details for PubMedID 23670900

  • F-18-Fluorobenzoate-Labeled Cystine Knot Peptides for PET Imaging of Integrin alpha(v)beta(6) JOURNAL OF NUCLEAR MEDICINE Hackel, B. J., Kimura, R. H., Miao, Z., Liu, H., Sathirachinda, A., Cheng, Z., Chin, F. T., Gambhir, S. S. 2013; 54 (7): 1101-1105
  • [F-18]CAIP a smart PET tracer for imaging caspase-3 induced Apoptosis Shen Bin, B., Jeon, J., Palner, M., Tong Ling, L., Felsher, D., Gambhir, S. S., Chin, F. T., Rao Jianghong, J. H. WILEY-BLACKWELL. 2013: S6–S6
  • Synthesis and initial evaluation of [F-18]CAIP for PET imaging of caspase-3 activity in apoptosis Jeon Jongho, J. H., Shen Bin, B., Palner, M., Ye Deju, D. J., Chin, F. T., Rao, J. WILEY-BLACKWELL. 2013: S375–S375
  • Improved [F-18]FEAU radiosynthesis on different automated radiochemistry platforms Shen, B., Lazari, M., Maraglia, B., Collier, L., Hammond, K., Moore, M., van Dam, R. M., Chin, F. T. WILEY-BLACKWELL. 2013: S471–S471
  • An efficient and site-specific F-18-labeling of biomolecules using a novel prosthetic group F-18-cyanobenzothiazole ([F-18]CBT) Jeon, J., Shen Bin, B., Su Xinhui, X. H., Cheng Zhen, Z., Rao Jianghong, J. H., Chin, F. T. WILEY-BLACKWELL. 2013: S177–S177
  • No-carrier-added [18F]fluoroarenes from the radiofluorination of diaryl sulfoxides. Chemical communications Chun, J., Morse, C. L., Chin, F. T., Pike, V. W. 2013; 49 (21): 2151-2153


    No-carrier-added [(18)F]fluoroarenes were synthesized through the radiofluorination of diaryl sulfoxides with [(18)F]fluoride ion. Diaryl sulfoxides bearing a para electron-withdrawing substituent readily gave the corresponding 4-[(18)F]fluoroarenes in high RCYs. This process broadens the scope for preparing novel (18)F-labeling synthons and PET radiotracers.

    View details for DOI 10.1039/c3cc37795d

    View details for PubMedID 23388835

  • [F-18]CAIP: a novel PET tracer for imaging caspase-3-initiated apoptosis in treated tumors Palner, M., Shen, B., Jeon, J., Ye, D., Shuhendler, A., Chin, F. T., Rao, J. SOC NUCLEAR MEDICINE INC. 2013: 20–20
  • Dissection of the role of the tumor microenvironment in oncogene addiction by ex vivo and in situ imaging Tong, L., Jeon, J., Shen, B., Jianghong, R., Chin, F., Gambhir, S., Felsher, D. SOC NUCLEAR MEDICINE INC. 2013: 25–25
  • Synthesis of ligand-functionalized water-soluble [F-18]YF3 nanoparticles for PET imaging NANOSCALE Xiong, L., Shen, B., Behera, D., Gambhir, S. S., Chin, F. T., Rao, J. 2013; 5 (8): 3253-3256


    We report a simple, efficient synthesis of novel (18)F-labeled imaging agents based on YF3 nanoparticles. Targeting ligands and antitumor drug molecules can be introduced onto the YF3 nanoparticles in a one-pot synthesis. The (18)F-labeling reaction proceeds in aqueous solutions at room temperature with excellent radiolabeling yields (>80%) in a very short time (5-10 min). (18)F-labeled YF3 nanoparticles displayed high stability in mouse and human serum, and their application for mapping lymph nodes in live rats after local injection has also been demonstrated.

    View details for DOI 10.1039/c3nr00335c

    View details for Web of Science ID 000316959500019

    View details for PubMedID 23508229

  • New Positron Emission Tomography (PET) Radioligand for Imaging sigma-1 Receptors in Living Subjects JOURNAL OF MEDICINAL CHEMISTRY James, M. L., Shen, B., Zavaleta, C. L., Nielsen, C. H., Mesangeau, C., Vuppala, P. K., Chan, C., Avery, B. A., Fishback, J. A., Matsumoto, R. R., Gambhir, S. S., McCurdy, C. R., Chin, F. T. 2012; 55 (19): 8272-8282


    ?-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination, and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([(18)F]FTC-146, [(18)F]13). [(18)F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/?mol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [(18)F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pretreatment with 1 mg/kg haloperidol (2), nonradioactive 13, or BD1047 (18) reduced the binding of [(18)F]13 in the brain at 60 min by 80%, 82%, and 81%, respectively, suggesting that [(18)F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [(18)F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.

    View details for DOI 10.1021/jm300371c

    View details for Web of Science ID 000309643500008

    View details for PubMedID 22853801

  • alpha v beta 3 Integrins as a Biomarker of Disease Recurrence in Glioblastoma Multiforme: Initial Clinical Results Using 18F FPPRGD2 PET/CT Iagaru, A., Mosci, C., Mittra, E. S., Shin, B., Chin, F., Gambhir, S. S. SPRINGER. 2012: S244–S245
  • Efficient Method for Site-Specific F-18-Labeling of Biomolecules Using the Rapid Condensation Reaction between 2-Cyanobenzothiazole and Cysteine BIOCONJUGATE CHEMISTRY Jeon, J., Shen, B., Xiong, L., Miao, Z., Lee, K. H., Rao, J., Chin, F. T. 2012; 23 (9): 1902-1908


    An efficient method based on a rapid condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine has been developed for (18)F-labeling of N-terminal cysteine-bearing peptides and proteins. An (18)F-labeled dimeric cRGD ([(18)F]CBTRGD(2)) has been synthesized with an excellent radiochemical yield (92% based on radio-HPLC conversion, 80% decay-corrected, and isolated yield) and radiochemical purity (>99%) under mild conditions using (18)F-CBT, and shown good in vivo tumor targeting efficiency for PET imaging. The labeling strategy was also applied to the site-specific (18)F-labeling of a protein, Renilla lucifierase (RLuc8) with a cysteine residue at its N-terminus. The protein labeling was achieved with 12% of decay-corrected radiochemical yield and more than 99% radiochemical purity. This strategy should provide a general approach for efficient and site-specific (18)F-labeling of various peptides and proteins for in vivo molecular imaging applications.

    View details for DOI 10.1021/bc300273m

    View details for Web of Science ID 000308833600021

    View details for PubMedID 22845703

  • Direct high yield no-carrier added radiosynthesis of [F-18]catecholamines Miao, Z., Shen, B., Qin, L., Neumann, K., DiMagno, S., Chin, F. T. NATURE PUBLISHING GROUP. 2012: S191–S191
  • First Experience with Clinical-Grade [F-18]FPP(RGD)(2): An Automated Multi-step Radiosynthesis for Clinical PET Studies MOLECULAR IMAGING AND BIOLOGY Chin, F. T., Shen, B., Liu, S., Berganos, R. A., Chang, E., Mittra, E., Chen, X., Gambhir, S. S. 2012; 14 (1): 88-95


    A reliable and routine process to introduce a new ¹?F-labeled dimeric RGD-peptide tracer ([¹?F]FPP(RGD?) for noninvasive imaging of ?(v)?? expression in tumors needed to be developed so the tracer could be evaluated for the first time in man. Clinical-grade [¹?F]FPP(RGD)? was screened in mouse prior to our first pilot study in human.[¹?F]FPP(RGD)? was synthesized by coupling 4-nitrophenyl-2-[¹?F]fluoropropionate ([¹?F]NPE) with the dimeric RGD-peptide (PEG?-c(RGDyK)?). Imaging studies with [¹?F]FPP(RGD)? in normal mice and a healthy human volunteer were carried out using small animal and clinical PET scanners, respectively.Through optimization of each radiosynthetic step, [¹?F]FPP(RGD)? was obtained with RCYs of 16.9?±?2.7% (n?=?8, EOB) and specific radioactivity of 114?±?72 GBq/?mol (3.08?±?1.95 Ci/?mol; n?=?8, EOB) after 170 min of radiosynthesis. In our mouse studies, high radioactivity uptake was only observed in the kidneys and bladder with the clinical-grade tracer. Favorable [¹?F]FPP(RGD)? biodistribution in human studies, with low background signal in the head, neck, and thorax, showed the potential applications of this RGD-peptide tracer for detecting and monitoring tumor growth and metastasis.A reliable, routine, and automated radiosynthesis of clinical-grade [¹?F]FPP(RGD)? was established. PET imaging in a healthy human volunteer illustrates that [¹?F]FPP(RGD)? possesses desirable pharmacokinetic properties for clinical noninvasive imaging of ?(v)?? expression. Further imaging studies using [¹?F]FPP(RGD)? in patient volunteers are now under active investigation.

    View details for DOI 10.1007/s11307-011-0477-3

    View details for Web of Science ID 000301583900012

    View details for PubMedID 21400112

  • Molecular Imaging of Hypoxia: Strategies for Probe Design and Application CURRENT ORGANIC SYNTHESIS Apte, S., Chin, F. T., Graves, E. E. 2011; 8 (4): 593-603


    Tumor hypoxia is a negative prognostic factor and its precise imaging is of great relevance to therapy planning. The present review summarizes various strategies of probe design for imaging hypoxia with a variety of techniques such as PET, SPECT and fluorescence imaging. Synthesis of some important probes that are used for preclinical and clinical imaging and their mechanism of binding in hypoxia are also discussed.

    View details for Web of Science ID 000294410500009

  • Recent Progress in Radiofluorination of Peptides for PET Molecular Imaging CURRENT ORGANIC SYNTHESIS Liu, S., Shen, B., Chin, F. T., Cheng, Z. 2011; 8 (4): 584-592
  • Pilot Pharmacokinetic and Dosimetric Studies of F-18-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging alpha(v)beta(3) Integrin Levels RADIOLOGY Mittra, E. S., Goris, M. L., Iagaru, A. H., Kardan, A., Burton, L., Berganos, R., Chang, E., Liu, S., Shen, B., Chin, F. T., Chen, X., Gambhir, S. S. 2011; 260 (1): 182-191


    To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fluorine 18 ((18)F) FPPRGD2 (2-fluoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets ?(v)?(3) integrin, in the first volunteers imaged with this tracer.The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi ± 3.4 [standard deviation] [351.5 MBq ± 125.8]; mean specific radioactivity, 1200 mCi/mmol ± 714 [44.4 GBq/mmol ± 26.4]). During this time, standard vital signs, electrocardiographic (ECG) readings, and blood sample values (for chemistry, hematologic, and liver function tests) were checked at regular intervals and 1 and 7 days after the injection. These data were used to evaluate tracer biodistribution and dosimetric properties, time-activity curves, and the stability of laboratory values. Significant changes in vital signs and laboratory values were evaluated by using a combination of population-averaged generalized estimating equation regression and exact paired Wilcoxon tests.The administration of (18)F-FPPRGD2 was well tolerated, with no marked effects on vital signs, ECG readings, or laboratory values. The tracer showed the same pattern of biodistribution in all volunteers: primary clearance through the kidneys (0.360 rem/mCi ± 0.185 [0.098 mSv/MBq ± 0.050]) and bladder (0.862 rem/mCi ± 0.436 [0.233 mSv/MBq ± 0.118], voiding model) and uptake in the spleen (0.250 rem/mCi ± 0.168 [0.068 mSv/MBq ± 0.046]) and large intestine (0.529 rem/mCi ± 0.236 [0.143 mSv/MBq ± 0.064]). The mean effective dose of (18)F-FPPRGD2 was 0.1462 rem/mCi ± 0.0669 (0.0396 mSv/MBq ± 0.0181). With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% ± 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 ± 0.096).(18)F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties. The primary application is likely to be PET evaluation of oncologic patients-especially those with brain, breast, or lung cancer. Specific indications may include tumor staging, identifying patients who would benefit from antiangiogenesis therapy, and separating treatment responders from nonresponders early.

    View details for DOI 10.1148/radiol.11101139

    View details for Web of Science ID 000291932300021

    View details for PubMedID 21502381

  • F-18-5-fluorouracil dynamic positron emission tomography/computed tomography shows decreased tracer activity after bevacizumab in colorectal metastases NUCLEAR MEDICINE COMMUNICATIONS Zissen, M. H., Kunz, P., Subbarayan, M., Chin, F. T., Conti, P. S., Fisher, G. A., Quon, A. 2011; 32 (5): 343-347


    The aim of this study was to evaluate the potential of fluorine-18 (F)-5-fluorouracil (F-5-FU) positron emission tomography/computed tomography (PET/CT) to show differences in 5-FU activity in metastatic colorectal cancer before and after treatment with bevacizumab.This was a pilot study of five patients with newly diagnosed and untreated metastatic colorectal adenocarcinoma. The presence of cancer was confirmed by histopathological analysis before enrollment. Patients underwent F-5-FU PET/CT scanning before treatment and at approximately 24 h postbevacizumab. PET/CT scanning consisted of a dynamic acquisition of images taken 0-20 min after injection of radiotracer. The degree of F-5-FU activity at the metastatic sites was assessed using visual interpretation and semiquantitative standardized uptake value analyses.The sizes of the metastatic lesions ranged from the smallest lesion measuring 3.04 × 1.50 cm to the largest measuring 4.19 × 2.76 cm. By drawing regions of interest, time-activity curves were generated at each tumor site and area under the curve (AUC) analyses were carried out. At baseline, during the first 5 min after F-5-FU injection the mean AUCtumor/AUCaorta ratio was 1.24 ± 0.30 (range, 0.424-2.14). Less than 24 h after the administration of bevacizumab, the AUCtumor/AUCaorta ratio decreased to 1.06 ± 0.32 (range, 0.23-2.13, P=0.04), which represented an average decline of 20.2% (range, 0.4-45%). Radiotracer uptake on the 5, 10, 15, and 20-min images did not show any significant change between baseline and posttreatment. Follow-up CT imaging showed stable tumor size in one patient and a decrease in metastasis size in the remaining four patients.In this pilot study of five patients with metastatic colorectal carcinoma, F-5-FU PET/CT scanning showed a significant perfusion-related decrease in tracer activity 24 h postbevacizumab.

    View details for DOI 10.1097/MNM.0b013e328344894b

    View details for Web of Science ID 000289761500003

    View details for PubMedID 21412178

  • Metabolic stability of 6,7-dialkoxy-4-(2-, 3-and 4-[F-18]fluoroanilino)quinazolines, potential EGFR imaging probes BIOORGANIC & MEDICINAL CHEMISTRY Vasdev, N., Dorff, P. N., O'Neil, J. P., Chin, F. T., Hanrahan, S., VanBrocklin, H. F. 2011; 19 (9): 2959-2965


    Epidermal growth factor receptors (EGFR), upregulated in many tumor types, have been a target for therapeutic development and molecular imaging. The objective of this study was to evaluate the distribution and metabolic characteristics of fluorine-18 labeled anilinoquinazolines as potential imaging agents for EGFR tyrosine kinase expression. Fluorine-18 labeled fluoronitrobenzenes were prepared by reaction of potassium cryptand [(18)F]fluoride with 1,2- and 1,4-dinitrobenzenes, and 3-nitro-N,N,N-trimethylanilinium triflate in 5min. Decay-corrected radiochemical yields of [(18)F]fluoride incorporation into the nitro-aromatic compounds were 81±2%, 44±4% and 77±5% (n=3-5) for the 2-, 3- and 4-fluoro isomers, respectively. Sodium borohydride reduction to the corresponding [(18)F]fluoroanilines was achieved with greater than 80% conversion in 5min. Coupling of [(18)F]fluoroaniline-hydrochlorides to 6,7-dimethoxy-4-chloro-quinazoline gave the corresponding 6,7-dimethoxy-4-(2-, 3- and 4-[(18)F]fluoroanilino)quinazolines in 31±5%, 17±2% and 55±2% radiochemical yield, respectively, while coupling to the 6,7-diethoxy-4-chloro-quinazoline produced 6,7-diethoxy-4-(2-, 3- and 4-[(18)F]fluoroanilino)quinazolines in 19±6%, 9±3% and 36±6% radiochemical yield, respectively, in 90min to end of synthesis from [(18)F]fluoride. Biodistribution of 2- and 4-[(18)F]fluoroanilinoquinazolines was conducted in tumor-bearing mice (MDA-MB-435 and MDA-MB-468 xenografts). Low tumor uptake (<1% injected dose per gram (ID/g) of tissue up to 3h postinjection of the radiotracers) was observed. High bone uptake (5-15% ID/g) was noted with the 4-[(18)F]fluoroanilinoquinazolines. The metabolic stabilities of radiolabeled quinazolines were further evaluated by incubation with human female cryopreserved isolated hepatocytes. Rapid degeneration of the 4-fluoro-substituted compounds to baseline polar metabolites was observed by radio-TLC, whereas, the 2- and 3-[(18)F]fluoroaniline derivatives were significantly more stable, up to 2h, corroborating the in vivo biodistribution studies. para-Substituted [(18)F]fluoroanilines, a common structural motif in radiopharmaceuticals, are highly susceptible to metabolic degradation.

    View details for DOI 10.1016/j.bmc.2011.03.032

    View details for Web of Science ID 000289834600019

    View details for PubMedID 21478021

  • Reproducibility study of [F-18]FPP(RGD)(2) uptake in murine models of human tumor xenografts EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Chang, E., Liu, S., Gowrishankar, G., Yaghoubi, S., Wedgeworth, J. P., Chin, F., Berndorff, D., Gekeler, V., Gambhir, S. S., Cheng, Z. 2011; 38 (4): 722-730


    An (18)F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer {[(18)F]FPP(RGD)(2)} has been used to image tumor ?(v)?(3) integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin ?(v)?(3)-targeted PET probe, [(18)F]FPP(RGD)(2,) using small animal PET.Human HCT116 colon cancer xenografts were implanted into nude mice (n?=?12) in the breast and scapular region and grown to mean diameters of 5-15 mm for approximately 2.5 weeks. A 3-min acquisition was performed on a small animal PET scanner approximately 1 h after administration of [(18)F]FPP(RGD)(2) (1.9-3.8 MBq, 50-100 ?Ci) via the tail vein. A second small animal PET scan was performed approximately 6 h later after reinjection of the probe to assess for reproducibility. Images were analyzed by drawing an ellipsoidal region of interest (ROI) around the tumor xenograft activity. Percentage injected dose per gram (%ID/g) values were calculated from the mean or maximum activity in the ROIs. Coefficients of variation and differences in %ID/g values between studies from the same day were calculated to determine the reproducibility.The coefficient of variation (mean±SD) for %ID(mean)/g and %ID(max)/g values between [(18)F]FPP(RGD)(2) small animal PET scans performed 6 h apart on the same day were 11.1?±?7.6% and 10.4?±?9.3%, respectively. The corresponding differences in %ID(mean)/g and %ID(max)/g values between scans were -0.025?±?0.067 and -0.039?±?0.426. Immunofluorescence studies revealed a direct relationship between extent of ?(?)?(3) integrin expression in tumors and tumor vasculature with level of tracer uptake. Mouse body weight, injected dose, and fasting state did not contribute to the variability of the scans; however, consistent scanning parameters were necessary to ensure accurate studies, in particular, noting tumor volume, as well as making uniform: the time of imaging after injection and the ROI size. Reanalysis of ROI placement displayed variability for %ID(mean)/g of 6.6?±?3.9% and 0.28?±?0.12% for %ID(max)/g.[(18)F]FPP(RGD)(2) small animal PET mouse tumor xenograft studies are reproducible with relatively low variability.

    View details for DOI 10.1007/s00259-010-1672-1

    View details for Web of Science ID 000288255500015

    View details for PubMedID 21125268

  • Radiolabeling of a Saxitoxin derivative for PET-MRI imaging of pain Hoehne, A., Parsons, W. H., Behera, D., Shen, B., Gambhir, S. S., Du Bois, J., Biswal, S., Chin, F. T. WILEY-BLACKWELL. 2011: S2–S2
  • No-carrier-added radiosyntheses of [F-18]fluoroarenes from diaryl sulfoxides and [F-18]fluoride ion Chun, J., Morse, C. L., Chin, F. T., Pike, V. W. WILEY-BLACKWELL. 2011: S70–S70
  • [F-18]YF3 nanoprobes: a novel synthetic strategy for F-18-labeled imaging agents Xiong Liqin, L. Q., Shen Bin, B., Gambhir, S. S., Chin, F. T., Rao Jianghong, J. H. WILEY-BLACKWELL. 2011: S77–S77
  • F-18-Cyanobenzolthiol ([F-18]CBT): A novel F-18-prosthetic group for labeling peptide or protein Shen Bin, B., Jeon, J., Gambhir, S. S., Rao, J., Chin, F. T. WILEY-BLACKWELL. 2011: S503–S503
  • PET imaging of cerebral ischemia-induced neuroinflammation in mice using F-18-PBR06 Lartey, F. M., Ahn, G., Shen, B., Cord, K., Smith, T., Chua, J. Y., Rosenblum, S., Tirouvanziam, R., Palmer, T., Guzman, R., Chin, F. T., Graves, E., Loo, B. W. WILEY-BLACKWELL. 2011: S319–S319
  • [F-18]FTC-146 for imaging sigma-1 receptors in squirrel monkey brain using PET/MRI James, M. L., Shen, B., Nielsen, C. H., Buckmaster, C. L., Berganos, R. A., Zavaleta, C., Lyons, D., McCurdy, C. R., Gambhir, S. S., Chin, F. T. WILEY-BLACKWELL. 2011: S317–S317
  • 18F-labeled galacto and PEGylated RGD dimers for PET imaging of avß3 integrin expression. Molecular imaging and biology Liu, S., Liu, Z., Chen, K., Yan, Y., Watzlowik, P., Wester, H., Chin, F. T., Chen, X. 2010; 12 (5): 530-538


    In vivo imaging of α(v)β(3) has important diagnostic and therapeutic applications. (18)F-Galacto-arginine-glycine-aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin α(v)β(3) expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin α(v)β(3)-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used (18)F-galacto-RGD.RGD monomers and dimers were coupled with galacto or PEG(3) linkers, and labeled with (18)F using 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP) or N-succinimidyl 4-(18)F-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model.Starting with (18)F-F(-), the total reaction time for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 are 52 ± 9% and 80 ± 7% calculated from (18)F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to (18)F-galacto-RGD.Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin α(v)β(3) imaging.

    View details for DOI 10.1007/s11307-009-0284-2

    View details for PubMedID 19949981

  • F-18-Labeled Galacto and PEGylated RGD Dimers for PET Imaging of alpha(v)beta(3) Integrin Expression MOLECULAR IMAGING AND BIOLOGY Liu, S., Liu, Z., Chen, K., Yan, Y., Watzlowik, P., Wester, H., Chin, F. T., Chen, X. 2010; 12 (5): 530-538
  • [F-18]FPPRGD2 PET/CT Imaging of Integrin Expression in Healthy Volunteers Mittra, E., Iagaru, A., Goris, M. L., Chin, F., Chen, X., Gambhir, S. S. SPRINGER. 2010: S287–S287
  • [F-18]FTC-146: A novel and highly selective PET ligand for visualizing sigma-1 receptors in living subjects James, M. L., Shen, B., Zavaleta, C., Berganos, R. A., Mesangeau, C., Shaikh, J., Gambhir, S. S., Matsumoto, R. R., McCurdy, C. R., Chin, F. T. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2010: S123–S124
  • PET of Malignant Melanoma Using F-18-Labeled Metallopeptides JOURNAL OF NUCLEAR MEDICINE Ren, G., Liu, Z., Miao, Z., Liu, H., Subbarayan, M., Chin, F. T., Zhang, L., Gambhir, S. S., Cheng, Z. 2009; 50 (11): 1865-1872


    Melanocortin type 1 receptor (MC1R), also known as alpha-melanocyte-stimulating hormone (alpha-MSH) receptor, is an attractive molecular target for melanoma imaging and therapy. An (18)F-labeled linear alpha-MSH peptide ((18)F-FB-Ac-Nle-Asp-His-d-Phe-Arg-Trp-Gly-Lys-NH(2) [NAPamide]) shows promising melanoma imaging properties but with only moderate tumor uptake and retention. A transition metal rhenium-cyclized alpha-MSH peptide, ReO[Cys(3,4,10),d-Phe(7),Arg(11)]alpha-MSH(3-13) (ReCCMSH(Arg(11))), has shown high in vitro binding affinity to MC1R and excellent in vivo melanoma-targeting profiles when labeled with radiometals. Therefore, we hypothesized that ReCCMSH(Arg(11)) could be a good platform for the further development of an (18)F-labeled probe for PET of MC1R-positive malignant melanoma.In this study, the metallopeptide Ac-d-Lys-ReCCMSH(Arg(11)) was synthesized using conventional solid-phase peptide synthesis chemistry and a rhenium cyclization reaction. The resulting peptides were then labeled with N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB). The (18)F-labeled metallopeptides were further tested for their in vitro receptor binding affinities, in vivo biodistribution, and PET imaging properties.Both isomers of Ac-d-Lys-ReCCMSH(Arg(11)), named as RMSH-1 and RMSH-2, were purified and identified by high-performance liquid chromatography. The binding affinities of RMSH-1 and RMSH-2 and their respective (19)F-SFB-conjugated peptides ((19)F-FB-RMSH-1 and (19)F-FB-RMSH-2) were all determined to be within nanomolar range. Both (18)F-labeled metallopeptides showed good tumor uptake in the B16F10 murine model, with high MC1R expression, but much lower uptake in the A375M human melanoma xenografted in mice, indicating low MC1R expression. (18)F-FB-RMSH-1, when compared with (18)F-FB-RMSH-2, displayed more favorable in vivo performance in terms of slightly higher tumor uptakes and much lower accumulations in the kidney and liver at 2 h after injection. Small-animal PET of (18)F-FB-RMSH-1 and -2 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptakes and poorer tumor-to-normal organ contrasts were observed for the A375M model than for the B16F10 model. (18)F-FB-RMSH-1 and -2 showed higher tumor uptake and better tumor retention than did (18)F-FB-NAPamide.Specific in vivo targeting of (18)F-FB-RMSH-1 to malignant melanoma was successfully achieved in preclinical models with high MC1R expression. Thus, the radiofluorinated metallopeptide (18)F-FB-RMSH-1 is a promising molecular probe for PET of MC1R-positive tumors.

    View details for DOI 10.2967/jnumed.109.062877

    View details for Web of Science ID 000272554100021

    View details for PubMedID 19837749

  • Dual Integrin and Gastrin-Releasing Peptide Receptor Targeted Tumor Imaging Using F-18-labeled PEGylated RGD-Bombesin Heterodimer F-18-FB-PEG(3)-Glu-RGD-BBN JOURNAL OF MEDICINAL CHEMISTRY Liu, Z., Yan, Y., Chin, F. T., Wang, F., Chen, X. 2009; 52 (2): 425-432


    Radiolabeled RGD and bombesin peptides have been extensively investigated for tumor integrin alpha(v)beta(3) and GRPR imaging, respectively. Due to the fact that many tumors are both integrin and GRPR positive, we designed and synthesized a heterodimeric peptide Glu-RGD-BBN, which is expected to be advantageous over the monomeric peptides for dual-receptor targeting. A PEG(3) spacer was attached to the glutamate alpha-amino group of Glu-RGD-BBN to enhance the (18)F labeling yield and to improve the in vivo kinetics. PEG(3)-Glu-RGD-BBN possesses the comparable GRPR and integrin alpha(v)beta(3) receptor-binding affinities as the corresponding monomers, respectively. The dual-receptor targeting properties of (18)F-FB-PEG(3)-Glu-RGD-BBN were observed in PC-3 tumor model. (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging. This heterodimer strategy may also be an applicable method to develop other molecules with improved in vitro and in vivo characterizations for tumor diagnosis and therapy.

    View details for DOI 10.1021/jm801285t

    View details for Web of Science ID 000262522100022

    View details for PubMedID 19113865

  • AUTOMATED RADIOSYNTHESIS OF [F-18]EF-5 FOR IMAGING HYPOXIA IN HUMAN Chin, F. T., Subbarayan, M., Sorger, J., Gambhir, S. S., Graves, E. E. WILEY-BLACKWELL. 2009: S274–S274
  • Initial evaluation of F-18-fluorothymidine (FLT) PET/CT scanning for primary pancreatic cancer EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Quon, A., Chang, S. T., Chin, F., Kamaya, A., Dick, D. W., Loo, B. W., Gambhir, S. S., Koong, A. C. 2008; 35 (3): 527-531


    The aim of this study was to evaluate the potential of (18)F-fluorothymidine (FLT) PET/CT for imaging pancreatic adenocarcinoma.This was a pilot study of five patients (four males, one female) with newly diagnosed and previously untreated pancreatic adenocarcinoma. Patients underwent FLT PET/CT, (18)F-fluorodeoxyglucose (FDG) PET/CT, and contrast-enhanced CT scanning before treatment. The presence of cancer was confirmed by histopathological analysis at the time of scanning in all five patients. The degree of FLT and FDG uptake at the primary tumor site was assessed using visual interpretation and semi-quantitative SUV analyses.The primary tumor size ranged from 2.5 x 2.8 cm to 3.5 x 7.0 cm. The SUV of FLT uptake within the primary tumor ranged from 2.1 to 3.1. Using visual interpretation, the primary cancer could be detected from background activity in two of five patients (40%) on FLT PET/CT. By comparison, FDG uptake was higher in each patient with a SUV range of 3.4 to 10.8, and the primary cancer could be detected from background in all five patients (100%).In this pilot study of five patients with primary pancreatic adenocarcinoma, FLT PET/CT scanning showed poor lesion detectability and relatively low levels of radiotracer uptake in the primary tumor.

    View details for DOI 10.1007/s00259-007-0630-z

    View details for Web of Science ID 000254402800010

    View details for PubMedID 17960376

  • Semiautomated radiosynthesis and biological evaluation of [F-18]FEAU: A novel PET imaging agent for HSV1-tk/sr39tk reporter gene expression MOLECULAR IMAGING AND BIOLOGY Chin, F. T., Namavari, M., Levi, J., Subbarayan, M., Ray, P., Chen, X., Gambhir, S. S. 2008; 10 (2): 82-91


    2'-deoxy-2'-[(18)F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil ([(18)F]FEAU) is a promising radiolabeled nucleoside designed to monitor Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography (PET). However, the challenging radiosynthesis creates problems for being able to provide [(18)F]FEAU routinely. We have developed a routine method using a commercial GE TRACERlab FX-FN radiosynthesis module with customized equipment to provide [(18)F]FEAU. All radiochemical yields are decay corrected to end-of-bombardment and reported as means +/- SD. Radiofluorination (33 +/- 8%; n = 4), bromination (85 +/- 8%; n = 4), coupling reaction (83 +/- 6%; n = 4), base hydrolysis steps, and subsequent high-performance liquid chromatography purification afforded purified [(18)F]FEAU beta-anomer in 5 +/- 1% overall yield (n = 3 runs) after approximately 5.5 h and a beta/alpha-anomer ratio of 7.4. Radiochemical/chemical purities and specific activity exceeded 99% and 1.3 Ci/micromol (48 GBq/micromol), respectively. In cell culture, [(18)F]FEAU showed significantly (P < 0.05) higher accumulation in C6 cells expressing HSV1-tk/sr39tk as compared to wild-type C6 cells. Furthermore, [(18)F]FEAU showed slightly higher accumulation than 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butylguanine ([(18)F]FHBG) in cells expressing HSV1-tk (P < 0.05), whereas [(18)F]FHBG showed significantly higher (P < 0.05) accumulation than [(18)F]FEAU in HSV1-sr39tk-expressing cells. micro-PET imaging of mice carrying tumor xenografts of C6 cells stably expressing HSV1-tk or HSV1-sr39tk are consistent with the cell uptake results. The [(18)F]FEAU mouse images also showed very low gastrointestinal signal with predominant renal clearance as compared to [(18)F]FHBG. The routine radiosynthesis of [(18)F]FEAU was successfully semiautomated using a commercial module along with customized equipment to provide the beta-anomer in modest yields. Although further studies are needed, early results also suggest [(18)F]FEAU is a promising PET radiotracer for monitoring HSV1-tk reporter gene expression.

    View details for DOI 10.1007/s11307-007-0122-3

    View details for Web of Science ID 000253192500003

    View details for PubMedID 18157580

  • F-18-labeled mini-PEG spacered RGD dimer (F-18-FPRGD2): synthesis and microPET imaging of alpha(v)beta(3) integrin expression EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Wu, Z., Li, Z., Cai, W., He, L., Chin, F. T., Li, F., Chen, X. 2007; 34 (11): 1823-1831


    We have previously reported that (18)F-FB-E[c(RGDyK)](2) ((18)F-FRGD2) allows quantitative PET imaging of integrin alpha(v)beta(3) expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer.(18)F-FB-mini-PEG-E[c(RGDyK)](2) ((18)F-FPRGD2) was synthesized by coupling N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) with NH(2)-mini-PEG-E[c(RGDyK)](2) (denoted as PRGD2). In vitro receptor binding affinity, metabolic stability, and integrin alpha(v)beta(3) specificity of the new tracer (18)F-FPRGD2 were assessed. The diagnostic value of (18)F-FPRGD2 was evaluated in subcutaneous U87MG glioblastoma xenografted mice and in c-neu transgenic mice by quantitative microPET imaging studies.The decay-corrected radiochemical yield based on (18)F-SFB was more than 60% with radiochemical purity of >99%. (18)F-FPRGD2 had high receptor binding affinity, metabolic stability, and integrin alpha(v)beta(3)-specific tumor uptake in the U87MG glioma xenograft model comparable to those of (18)F-FRGD2. The kidney uptake was appreciably lower for (18)F-FPRGD2 compared with (18)F-FRGD2 [2.0 +/- 0.2%ID/g for (18)F-FPRGD2 vs 3.0 +/- 0.2%ID/g for (18)F-FRGD2 at 1 h post injection (p.i.)]. The uptake in all the other organs except the urinary bladder was at background level. (18)F-FPRGD2 also exhibited excellent tumor uptake in c-neu oncomice (3.6 +/- 0.1%ID/g at 30 min p.i.).Incorporation of a mini-PEG spacer significantly improved the overall radiolabeling yield of (18)F-FPRGD2. (18)F-FPRGD2 also had reduced renal uptake and similar tumor targeting efficacy as compared with (18)F-FRGD2. Further testing and clinical translation of (18)F-FPRGD2 are warranted.

    View details for DOI 10.1007/s00259-007-0427-0

    View details for Web of Science ID 000250205400015

    View details for PubMedID 17492285

  • Click chemistry for F-18-labeling of RGD peptides and microPET Imaging of tumor integrin alpha(v)beta(3) expression BIOCONJUGATE CHEMISTRY Li, Z., Wu, Z., Chen, K., Chin, F. T., Chen, X. 2007; 18 (6): 1987-1994


    The cell adhesion molecule integrin alpha vbeta 3 plays a key role in tumor angiogenesis and metastasis. A series of (18)F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine reactive prosthetic groups. In this study, we report the use of the Cu(I)-catalyzed Huisgen cycloaddition, also known as a click reaction, to label RGD peptides with (18)F by forming 1,2,3-triazoles. Nucleophilic fluorination of a toluenesulfonic alkyne provided (18)F-alkyne in high yield (nondecay-corrected yield: 65.0 +/- 1.9%, starting from the azeotropically dried (18)F-fluoride), which was then reacted with an RGD azide (nondecay-corrected yield: 52.0 +/- 8.3% within 45 min including HPLC purification). The (18)F-labeled peptide was subjected to microPET studies in murine xenograft models. Murine microPET experiments showed good tumor uptake (2.1 +/- 0.4%ID/g at 1 h postinjection (p.i.)) with rapid renal and hepatic clearance of (18)F-fluoro-PEG-triazoles-RGD 2 ( (18)F-FPTA-RGD2) in a subcutaneous U87MG glioblastoma xenograft model (kidney 2.7 +/- 0.8%ID/g; liver 1.9 +/- 0.4%ID/g at 1 h p.i.). Metabolic stability of the newly synthesized tracer was also analyzed (intact tracer ranging from 75% to 99% at 1 h p.i.). In brief, the new tracer (18)F-FPTA-RGD2 was synthesized with high radiochemical yield and high specific activity. This tracer exhibited good tumor-targeting efficacy and relatively good metabolic stability, as well as favorable in vivo pharmacokinetics. This new (18)F labeling method based on click reaction may also be useful for radiolabeling of other biomolecules with azide groups in high yield.

    View details for DOI 10.1021/bc700226v

    View details for Web of Science ID 000251166400039

    View details for PubMedID 18030991

  • MicroPET of tumor integrin alpha(v)beta(3) expression using F-18-Labeled PEGylated tetrameric RGD peptide (F-18-FPRGD4) JOURNAL OF NUCLEAR MEDICINE Wu, Z., Li, Z., Chen, K., Cai, W., He, L., Chin, F. T., Li, F., Chen, X. 2007; 48 (9): 1536-1544


    In vivo imaging of alpha(v)beta(3) expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin alpha(v)beta(3)-binding affinity due to the polyvalency effect. Here we report an example of (18)F-labeled tetrameric RGD peptide for PET of alpha(v)beta(3) expression in both xenograft and spontaneous tumor models.The tetrameric RGD peptide E{E[c(RGDyK)](2)}(2) was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate alpha-amino group. NH(2)-mini-PEG-E{E[c(RGDyK)](2)}(2) (PRGD4) was labeled with (18)F via the N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer (18)F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies.The decay-corrected radiochemical yield for (18)F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from (18)F-F(-). The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. (18)F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of (18)F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK).The tetrameric RGD peptide tracer (18)F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin alpha(v)beta(3) expression in cancer and other angiogenesis related diseases.

    View details for DOI 10.2967/jnumed.107.040816

    View details for Web of Science ID 000252894700042

    View details for PubMedID 17704249

  • PET imaging of neurokinin-1 receptors with [F-18]SPA-RQ in human subjects: Assessment of reference tissue models and their test-retest reproducibility SYNAPSE Yasuno, F., Sanabria, S. M., Burns, D., Hargreaves, R. J., Ghose, S., Ichise, M., Chin, F. T., Morse, C. L., Pike, V. W., Innis, R. B. 2007; 61 (4): 242-251


    [(18)F]SPA-RQ (substance P antagonist receptor quantifier) labels the substance P-preferring (NK(1)) receptor in human brain. A prior study showed that [(18)F]SPA-RQ brain uptake can be quantified with a reference tissue method and thereby avoid invasive blood sampling. The purposes of this study were to compare three different reference tissue methods and to assess test-retest reproducibility. Eight healthy subjects underwent two [(18)F]SPA-RQ scans. We calculated the binding potential (BP), which is proportional to receptor density, from both regional volume of interest and voxel-wise data. We compared three reference tissue methods: simplified reference tissue model, multilinear reference tissue model (MRTM), and its two-parameter version (MRTM2). The three methods generated equivalent values of regional BP, but MRTM2 was the most resistant to noise. Temporally stable values of BP were obtained with 240 min of imaging data. MRTM2 had excellent test-retest reproducibility, with high reliability (intraclass correlation > 0.9) and low variability (< 10%). In addition to regional volume of interest analysis, we also created parametric images of BP, variability, and reliability based on voxel-wise time-activity data. The reproducibility of parametric BP was also good, with variability < 20% and reliability > 0.7 in gray matter regions. In conclusion, a two-parameter reference tissue method (MRTM2) provided reproducible and reliable measurements of [(18)F]SPA-RQ brain uptake using 240 min of both regional and voxel-wise data.

    View details for DOI 10.1002/syn.20361

    View details for Web of Science ID 000244105900006

    View details for PubMedID 17230546

  • Human biodistribution and radiation dosimetry of the tachykinin NK1 antagonist radioligand [F-18]SPA-RQ: Comparison of thin-slice, bisected, and 2-dimensional planar image analysis JOURNAL OF NUCLEAR MEDICINE Sprague, D. R., Chin, F. T., Liow, J., Fujita, M., Burns, H. D., Hargreaves, R., Stubbs, J. B., Pike, V. W., Innis, R. B., Mozley, P. D. 2007; 48 (1): 100-107


    (18)F-Labeled substance P antagonist-receptor quantifier ([(18)F]SPA-RQ) [2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-[(2S,3S)-2-phenyl-piperidin-3-yl)amine] is a selective radioligand for in vivo quantification of tachykinin NK(1) receptors with PET. The aims of this study were to estimate the radiation safety profile and relative risks of [(18)F]SPA-RQ with 3 different methods of image analysis.Whole-body PET images were acquired in 7 healthy subjects after injection of 192 +/- 7 MBq (5.2 +/- 0.2 mCi) [(18)F]SPA-RQ. Emission images were serially acquired at multiple time-points from 0 to 120 min and approximately 180-240 min after injection. Urine samples were collected after each imaging session and for 24 h after the last scan to measure excreted radioactivity. Horizontal tomographic images were compressed to varying degrees in the anteroposterior direction to create 3 datasets: thin-slice, bisected, and 2-dimensional (2D) planar images. Regions of interest were drawn around visually identifiable source organs to generate time-activity curves for each dataset. Residence times were determined from these curves, and doses to individual organs and the body as a whole were calculated using OLINDA/EXM 1.0.The lungs, upper large intestine wall, small intestine, urinary bladder wall, kidneys, and thyroid had the highest radiation-absorbed doses. Biexponential fitting of mean bladder and urine activity showed that about 41% of injected activity was excreted via urine. Assuming a 2.4-h urine voiding interval, the calculated effective doses from thin-slice, bisected, and 2D planar images were 29.5, 29.3, and 32.3 microSv/MBq (109, 108, and 120 mrem/mCi), respectively.Insofar as effective dose is an accurate measure of radiation risk, all 3 methods of analysis provided quite similar estimates of risk to human subjects. The radiation dose was moderate and would potentially allow subjects to receive multiple PET scans in a single year. Individual organ exposures varied among the 3 methods, especially for structures asymmetrically located in an anterior or posterior position. Bisected and 2D planar images almost always provided higher organ dose estimates than thin-slice images. Thus, either the bisected or 2D planar method of analysis appears acceptable for quantifying human radiation burden, at least for radioligands with a relatively broad distribution in the body and not concentrated in a small number of radiation sensitive organs.

    View details for Web of Science ID 000243306800047

    View details for PubMedID 17204705

  • Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease STEM CELLS Rodriguez-Gomez, J. A., Lu, J., Velasco, I., Rivera, S., Zoghbi, S. S., Liow, J., Musachio, J. L., Chin, F. T., Toyama, H., Seidel, J., Green, M. V., Thanos, P. K., Ichise, M., Pike, V. W., Innis, R. B., McKay, R. D. 2007; 25 (4): 918-928


    The derivation of dopamine neurons is one of the best examples of the clinical potential of embryonic stem (ES) cells, but the long-term function of the grafted neurons has not been established. Here, we show that, after transplantation into an animal model, neurons derived from mouse ES cells survived for over 32 weeks, maintained midbrain markers, and had sustained behavioral effects. Microdialysis in grafted animals showed that dopamine (DA) release was induced by depolarization and pharmacological stimulants. Positron emission tomography measured the expression of presynaptic dopamine transporters in the graft and also showed that the number of postsynaptic DA D(2) receptors was normalized in the host striatum. These data suggest that ES cell-derived neurons show DA release and reuptake and stimulate appropriate postsynaptic responses for long periods after implantation. This work supports continued interest in ES cells as a source of functional DA neurons.

    View details for DOI 10.1634/stemcells.2006-0386

    View details for Web of Science ID 000245766400014

    View details for PubMedID 17170065

  • Automated radiosynthesis of [F-18]SPA-RQ for imaging human brain NK1 receptors with PET JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Chin, F. T., Morse, C. L., Shetty, H. U., Pike, V. W. 2006; 49 (1): 17-31

    View details for DOI 10.1002/jlcr.1016

    View details for Web of Science ID 000235287800003

  • Use of LC-MS-MS for the rapid, specific and sensitive quality control measurement of carrier in a PET radioligand: [F-18]FECNT JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Shetty, H. U., Chin, F. T., Musachio, J. L., Pike, V. W. 2005; 48 (13): 929-940

    View details for DOI 10.1002/jlcr.1006

    View details for Web of Science ID 000233847300001

  • Alternative methods for labeling the 5-HT1A receptor agonist, 1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piperazine (S14506), with carbon-11 or fluorine-18 JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Lu, S. Y., Hong, J., Musachio, J. L., Chin, F. T., Vermeulen, E. S., Wikstrom, H. V., Pike, V. W. 2005; 48 (13): 971-981

    View details for DOI 10.1002/jlcr.1009

    View details for Web of Science ID 000233847300004

  • Whole-body biodistribution and radiation dosimetry estimates for the PET dopamine transporter probe F-18-FECNT in non-human drimates NUCLEAR MEDICINE COMMUNICATIONS Tipre, D. N., Fujita, M., Chin, F. T., Seneca, N., Vines, D., Liow, J. S., Pike, V. W., Innis, R. B. 2004; 25 (7): 737-742


    2 beta-Carbomethoxy-3-(4-chlorophenyl)-8-(2-[18F]fluoroethyl)nortropane (18F-FECNT) is a selective radioligand for the in vivo quantification of dopamine transporters by using positron emission tomography. The aim of the current study was to quantify the distribution of radioactivity in three rhesus monkeys after the injection of approximately 185 MBq (5 mCi) of 18F-FECNT.Whole-body images were acquired at 23-30 time points for a total of 220 min following injection of the radioligand. Source organs were identified at each time point from planar images.The peak activities in planar images in the six identified source organs (expressed as per cent injected dose (%ID)) were lungs (16.5%ID at 2 min), kidneys (12.5%ID at 3 min), brain (9.5%ID at 6 min), liver (7.5%ID at 3 min), red bone marrow (3.5%ID at 12 min), and urinary bladder (2%ID at 98 min). Radiation absorbed doses were calculated using the gastrointestinal tract model in two ways: (1) assuming no urine voiding, and (2) using a dynamic bladder model with voiding intervals of 2.4 and 4.8 h. Using the gastrointestinal tract model and dynamic bladder model with a voiding interval 4.8 h, the three organs with highest exposure (in mu Gy.MBq(-1) (mrad.mCi(-1)) were kidneys 75.68 (280), lungs 44.86 (166) and urinary bladder 58.38 (216). Effective doses estimated with and without urine voiding were in the range 21.35-22.70 mu Gy.MBq(-1) (79-84 mrad.mCi(-1)).The estimated radiation burden of 18F-FECNT is relatively modest and would allow multiple scans per research subject per year.

    View details for DOI 10.1097/01.mnm.0000133074.64669.60

    View details for Web of Science ID 000222547500017

    View details for PubMedID 15208503

  • Synthesis and evaluation of two F-18-labeled 6-iodo-2-(4 '-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease JOURNAL OF MEDICINAL CHEMISTRY Cai, L. S., Chin, F. T., Pike, V. W., Toyama, H., Liow, J. S., Zoghbi, S. S., Modell, K., Briard, E., Shetty, H. U., Sinclair, K., Donohue, S., Tipre, D., Kung, M. P., Dagostin, C., Widdowson, D. A., Green, M., Gao, W., Herman, M. M., Ichise, M., Innis, R. B. 2004; 47 (9): 2208-2218


    This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

    View details for DOI 10.1021/jm030477w

    View details for Web of Science ID 000220918500005

    View details for PubMedID 15084119

  • Efficient O- and N-(beta-fluoroethylation)s with NCA [F-18]beta-fluoroethyl tosylate under microwave-enhanced conditions JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS Lu, S. Y., Chin, F. T., McCarron, J. A., Pike, V. W. 2004; 47 (5): 289-297

    View details for DOI 10.1002/jlcr.818

    View details for Web of Science ID 000221179000001

  • Syntheses of C-11- and F-18-labeled carboxylic esters within a hydrodynamically-driven micro-reactor LAB ON A CHIP Lu, S. Y., Watts, P., Chin, F. T., Hong, J., Musachio, J. L., Briard, E., Pike, V. W. 2004; 4 (6): 523-525


    Carboxylic esters were successfully labeled with one of two short-lived positron-emitters, carbon-11 or fluorine-18, within a hydrodynamically-driven micro-reactor. The non-radioactive methyl ester was obtained at room temperature; its yield increased with higher substrate concentration and with reduced infusion rate. Radioactive methyl ester was obtained from the reaction of (10 mM) with in 56% decay-corrected radiochemical yield (RCY) at an infusion rate of 10 microL min(-1), and when the infusion rate was reduced to 1 microL min(-1), the RCY increased to 88%. The synthesis of the non-radioactive fluoroethyl ester from and required heating of the micro-reactor on a heating block at 80 degrees C (14-17% RCY), whilst the corresponding radioactive from and was obtained in 10% RCY. The radioactive 'peripheral' benzodiazepine receptor ligand was obtained from the reaction of acid with labeling agent in 45% RCY at an infusion rate of 10 microL min(-1). When the infusion rate was reduced to 1 microL min(-1), the RCY increased to 65%. The results exemplify a new methodology for producing radiotracers for imaging with positron emission tomography that has many potential advantages, including a requirement for small quantities of substrates, enhanced reaction, rapid reaction optimisation and easy product purification.

    View details for DOI 10.1039/b407938h

    View details for Web of Science ID 000225382800001

    View details for PubMedID 15570360