CAP Profiles

Bio

Honors & Awards

  • Agnes Campbell Postgraduate Prizes, The University of Sydney (2009, 2010, 2011, 2012, 2013, 2014)
  • SIRO Top-up Scholarship, CSIRO Materials Science and Engineering, Ian Wark Laboratory (2010-2013)
  • The University Postgraduate Award Scholarship, The University of Sydney (2010-2014)
  • The John A Lamberton Scholarship, The University of Sydney (2010-2014)
  • The R J W Le Fèvre Research Travelling Scholarship, The School of Chemistry, University of Sydney (2013)

Boards, Advisory Committees, Professional Organizations

  • Member, World Molecular Imaging Society (2015 - Present)
  • Member, Royal Australian Chemical Society (2009 - Present)

Professional Education

  • Bachelor of Science, University Of Sydney (2010)
  • Doctor of Philosophy, University Of Sydney (2014)

Stanford Advisors

Contact

Research & Scholarship

Current Research and Scholarly Interests

My current research areas of interest include developing new strategies for: 1) novel radioligand and radiotracer development for various targets involved in brain cancer, 2) preclinical animal models of glioblastoma, and 3) clinical translation of useful radiopharmaceuticals for early-detection of disease and monitoring therapy.

Lab Affiliations

Publications

All Publications

  • F]DASA-23 for Imaging Tumor Glycolysis Through Noninvasive Measurement of Pyruvate Kinase M2. Molecular imaging and biology Beinat, C., Alam, I. S., James, M. L., Srinivasan, A., Gambhir, S. S. 2017

    Abstract

    A hallmark of cancer is metabolic reprogramming, which is exploited by cancer cells to ensure rapid growth and survival. Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key step in tumor metabolism and growth. Recently, we reported the radiosynthesis of the first positron emission tomography tracer for visualizing PKM2 in vivo-i.e., [(11)C]DASA-23. Due to the highly promising imaging results obtained with [(11)C]DASA-23 in rodent model glioblastoma, we set out to generate an F-18-labeled version of this tracer, with the end goal of clinical translation in mind. Herein, we report the radiosynthesis of 1-((2-fluoro-6-[(18)F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([(18)F]DASA-23) and our initial investigation of its binding properties in cancer cells.We synthesized [(18)F]DASA-23 via fluorination of 1-((2-fluoro-6-nitrophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine (10) with K[(18)F]F/K2.2.2 in N,N-dimethylformamide at 110 °C for 20 min. Subsequently, we evaluated uptake of [(18)F]DASA-23 in HeLa cervical adenocarcinoma cells and in vitro stability in human and mouse serum.We successfully prepared [(18)F]DASA-23 in 2.61 ± 1.54 % radiochemical yield (n = 10, non-decay corrected at end of synthesis) with a specific activity of 2.59 ± 0.44 Ci/μmol. Preliminary cell uptake experiments revealed high uptake in HeLa cells, which was effectively blocked by pretreating cells with the structurally distinct PKM2 activator, TEPP-46. [(18)F]DASA-23 remained intact in human and mouse serum up to 120 min.Herein, we have identified a F-18-labeled PKM2 specific radiotracer which shows potential for in vivo imaging. The promising cell uptake results reported herein warrant the further evaluation of [(18)F]DASA-23 for its ability to detect and monitor cancer noninvasively.

    View details for DOI 10.1007/s11307-017-1068-8

    View details for PubMedID 28236227

  • 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-?

    Abstract

    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 PubMedID 27826950

  • Effects of common anesthetic agents on [F-18] flumazenil binding to the GABA(A) 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

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

    View details for Web of Science ID 000387828200001

  • The Recent Development of alpha(7) Nicotinic Acetylcholine Receptor (nAChR) Ligands as Therapeutic Candidates for the Treatment of Central Nervous System (CNS) Diseases CURRENT PHARMACEUTICAL DESIGN Beinat, C., Banister, S. D., Herrera, M., Kassiou, M. 2016; 22 (14): 2134-2151

    Abstract

    Homomeric α7 nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation of cognitive processes such as memory and attention and have potential as therapeutic targets for the treatment of the cognitive deficits associated with schizophrenia. Though numerous α7 nAChR agonists have been developed, and several have progressed to clinical trials, these are derived from few common chemotypes. Consequently, many of these α7 nAChR clinical candidates share unfavorable side-effect profile. SEN12333 represents a novel chemotype for the development of α7 nAChR agonists, and exploration of this scaffold has produced structurally diverse ligands with promising pharmacological properties. This review will summarize structure-affinity and -activity relationships surrounding analogs of SEN12333.

    View details for DOI 10.2174/1381612822666160127114125

    View details for Web of Science ID 000375146900016

    View details for PubMedID 26818858

  • Pharmacology of Indole and Indazole Synthetic Cannabinoid Designer Drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA ACS CHEMICAL NEUROSCIENCE Banister, S. D., Moir, M., Stuart, J., Kevin, R. C., Wood, K. E., Longworth, M., Wilkinson, S. M., Beinat, C., Buchanan, A. S., Glass, M., Connor, M., McGregor, I. S., Kassiou, M. 2015; 6 (9): 1546-1559

    Abstract

    Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.

    View details for DOI 10.1021/acschemneuro.5b00112

    View details for Web of Science ID 000361505100006

    View details for PubMedID 26134475

  • Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135 ACS CHEMICAL NEUROSCIENCE Banister, S. D., Stuart, J., Kevin, R. C., Edington, A., Longworth, M., Wilkinson, S. M., Beinat, C., Buchanan, A. S., Hibbs, D. E., Glass, M., Connor, M., McGregor, I. S., Kassiou, M. 2015; 6 (8): 1445-1458

    View details for DOI 10.1021/acschemneuro.5b00107

    View details for Web of Science ID 000359967300021

  • Structure-activity relationships of synthetic cannabinoid designer drug RCS-4 and its regioisomers and C4 homologues FORENSIC TOXICOLOGY Banister, S. D., Stuart, J., Conroy, T., Longworth, M., Manohar, M., Beinat, C., Wilkinson, S. M., Kevin, R. C., Hibbs, D. E., Glass, M., Connor, M., McGregor, I. S., Kassiou, M. 2015; 33 (2): 355-366

    View details for DOI 10.1007/s11419-015-0282-9

    View details for Web of Science ID 000358055400015

  • The Therapeutic Potential of alpha(7) Nicotinic Acetylcholine Receptor (alpha(7) nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia CNS DRUGS Beinat, C., Banister, S. D., Herrera, M., Law, V., Kassiou, M. 2015; 29 (7): 529-542

    Abstract

    Homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple α7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical α7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other α7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of α7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology.

    View details for DOI 10.1007/s40263-015-0260-0

    View details for Web of Science ID 000360567900002

    View details for PubMedID 26242477

  • Structure-activity relationship studies of SEN12333 analogues: Determination of the optimal requirements for binding affinities at alpha 7 nAChRs through incorporation of known structural motifs EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Beinat, C., Reekie, T., Banister, S. D., O'Brien-Brown, J., Xie, T., Olson, T. T., Xiao, Y., Harvey, A., O'Connor, S., Coles, C., Grishin, A., Kolesik, P., Tsanaktsidis, J., Kassiou, M. 2015; 95: 277-301

    Abstract

    Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8).

    View details for DOI 10.1016/j.ejmech.2015.03.025

    View details for Web of Science ID 000354139900025

    View details for PubMedID 25827398

  • 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

    Abstract

    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

    View details for PubMedID 25725375

  • Recent Advances in the Development of Sigma-1 Receptor Ligands Australian Journal of Chemistry Manohar, M., Banister, S. D., Beinat, C., O'Brien-Brown, J., Kassiou, M. 2015; 68 (4): 600-609

    View details for DOI 10.1071/CH14590

  • 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

    View details for DOI 10.1016/j.ejmech.2015.02.004

  • Investigations of amide bond variation and biaryl modification in analogues of alpha 7 nAChR agonist SEN12333 EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Beinat, C., Reekie, T., Hibbs, D., Xie, T., Olson, T. T., Xiao, Y., Harvey, A., O'Connor, S., Coles, C., Tsanaktsidis, J., Kassiou, M. 2014; 84: 200-205

    Abstract

    Several lines of experimental evidence support the involvement of the α7 nAChR in schizophrenia and Alzheimer's disease. Modulators of the α7 nAChR have been extensively reviewed for the treatment of the cognitive deficits associated with these pathologies. SEN12333 represents a novel α7 nAChR agonist chemotype with potential for reduced side effects but requiring further SAR exploration. The present work investigates the amide bond of SEN12333, specifically its connectivity and replacement with the tetrazole functionality, a known cis amide isostere. The results reveal the original amide bond connectivity of SEN12333 to be favorable for binding affinity and agonist activity at α7 nAChRs. The use of a tetrazole isostere completely abolishes affinity and functional activity and suggests that SEN12333 binds in a linear conformation. Results reported herein also suggest the pyridine nitrogen within the terminal aromatic ring of SEN12333 is not essential for binding affinity or functional activity. Further SAR investigations involving manipulation of other moieties contained within SEN12333 are warranted.

    View details for DOI 10.1016/j.ejmech.2014.07.029

    View details for Web of Science ID 000341464500022

    View details for PubMedID 25019477

  • Structure-activity relationships of N-substituted 4-(trifluoromethoxy) benzamidines with affinity for GluN2B-containing NMDA receptors BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Beinat, C., Banister, S. D., Hoban, J., Tsanaktsidis, J., Metaxas, A., Windhorst, A. D., Kassiou, M. 2014; 24 (3): 828-830

    Abstract

    GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.

    View details for DOI 10.1016/j.bmcl.2013.12.087

    View details for Web of Science ID 000330120800022

    View details for PubMedID 24412068

  • A practical synthesis of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane TETRAHEDRON LETTERS Beinat, C., Banister, S. D., McErlean, C. S., Kassiou, M. 2013; 54 (39): 5345-5347

    View details for DOI 10.1016/j.tetlet.2013.07.092

    View details for Web of Science ID 000324013400018

  • Consequences of linker length alteration of the alpha 7 nicotinic acetylcholine receptor (nAChR) agonist, SEN12333 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Beinat, C., Banister, S. D., van Prehn, S., Doddareddy, M. R., Hibbs, D., Sako, M., Chebib, M., Thao Tran, T., Al-Muhtasib, N., Xiao, Y., Kassiou, M. 2012; 22 (7): 2380-2384

    Abstract

    A series of ligands based on SEN12333, containing either contracted or elongated alkyl chains, were synthesized and evaluated in molecular docking studies against a homology model of the α7 nicotinic acetylcholine receptor (nAChR) subtype. The predicted binding of all ligands was highly similar, with the exception of the analog containing a 5 methylene unit spacer. However, in vitro competition binding assays revealed that the ligands possessed dissimilar binding affinities, with a K(i) range of more than an order of magnitude (K(i)=0.50 to >10 μM), and only SEN12333 itself exhibited functional activity at the α7 nAChR.

    View details for DOI 10.1016/j.bmcl.2012.02.052

    View details for Web of Science ID 000301846100002

    View details for PubMedID 22410083

  • Trishomocubane as a scaffold for the development of selective dopamine transporter (DAT) ligands BIOORGANIC & MEDICINAL CHEMISTRY LETTERS Banister, S. D., Moussa, I. A., Beinat, C., Reynolds, A. J., Schiavini, P., Jorgensen, W. T., Kassiou, M. 2011; 21 (1): 38-41

    Abstract

    In our continued exploration of trishomocubane derivatives with central nervous system (CNS) activity, N-arylalkyl-8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (10-13) displaying affinity for the sigma (σ) receptor were also found, in several cases, to interact with the dopamine transporter (DAT). Compound 12 was identified as the first trishomocubane-derived high affinity DAT ligand (K(i) = 1.2 nM), with greater than 8300-fold selectivity over the monoamine transporters NET and SERT, and only low to moderate affinity for σ(1) and σ(2) receptors.

    View details for DOI 10.1016/j.bmcl.2010.11.075

    View details for Web of Science ID 000285544400002

    View details for PubMedID 21146989

  • Design, Synthesis, and Structure-Affinity Relationships of Regioisomeric N-Benzyl Alkyl Ether Piperazine Derivatives as sigma-1 Receptor Ligands JOURNAL OF MEDICINAL CHEMISTRY Moussa, I. A., Banister, S. D., Beinat, C., Giboureau, N., Reynolds, A. J., Kassiou, M. 2010; 53 (16): 6228-6239

    Abstract

    A series of N-(benzofuran-2-ylmethyl)-N'-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro sigma1 {[3H]+-pentazocine} and sigma2 ([3H]DTG) receptor binding profiles of piperazines 11-13 and 25-36 revealed several highly potent and sigma1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N'-(4'-methoxybenzyl)piperazine (13, Ki=2.7 nM, sigma2/sigma1=38) and N-(benzofuran-2-ylmethyl)-N'-(4'-(2''-fluoroethoxy)benzyl)piperazine (30, Ki=2.6 nM, sigma2/sigma1=187). Structural features for optimal sigma1 receptor affinity and selectivity over the sigma2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a sigma1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other sigma receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the sigma1 receptor in neurodegenerative processes.

    View details for DOI 10.1021/jm100639f

    View details for Web of Science ID 000280962700028

    View details for PubMedID 20662542

  • Insights into Structure-Activity Relationships and CNS Therapeutic Applications of NR2B Selective Antagonists - See more at: http://www.eurekaselect.com/72752/article#sthash.FVkeRGWN.dpuf Current Medicinal Chemistry Beinat, C., Banister, S., Moussa, I., Reynolds, A. J., McErlean, C. S., Kassiou, M. 2010 ; 17 (34): 4166-90
  • Development of Vesicular Acetylcholine Transporter Ligands: Molecular Probes for Alzheimers Disease - See more at: http://www.eurekaselect.com/71948/article#sthash.dsWtg2ps.dpuf Current Bioactive Compounds Giboureau, N., Aumann, K. M., Beinat, C., Kassiou, M. 2010; 27: 129-155