Bio

Honors & Awards


  • ISF Grant, Israeli Science Foundation (2006, 2011)
  • Personal achievement award, Pharmacologist Association of Israel (2005)
  • Dean’s Honour List, Hebrew University, Jerusalem, Israel (2001-2003)
  • The Jerusalem scholarship, Hebrew University, Jerusalem, Israel (2000)

Professional Education


  • Bachelor of Science, Hebrew University Of Jerusalem (2005)
  • Master of Science, Hebrew University Of Jerusalem (2006)
  • Doctor of Philosophy, Hebrew University Of Jerusalem (2012)

Stanford Advisors


Publications

Journal Articles


  • Structure-Activity Relationship and Preclinical Evaluation of Carbon-11-Labeled Ammonium Salts as PET-Myocardial Perfusion Imaging Agents MOLECULAR IMAGING AND BIOLOGY Ilovich, O., Abourbeh, G., Bocher, M., Freedman, N., Billauer, H., Dotan, S., Danenberg, H. D., Mishani, E. 2012; 14 (5): 625-636

    Abstract

    Due to the limited availability of suitable positron emission tomography (PET) tracers, the majority of myocardial perfusion imaging (MPI) scans is performed using SPECT rather than PET.The aim of this study is to design and synthesize carbon-11-labeled ammonium salt derivatives and explore their structure–activity relationship (SAR) and their potential as PET–MPI agents.Three carbon-11-labeled ammonium salts were developed. SAR of the labeled compounds were explored vis-à-vis the effects of charge density and lipophilicity on the distribution kinetics in mice. These studies pointed at [11C]4 as the lead compound. Comparative microPET/CT scans in healthy rats, using both [11C]4 and [13?N]–NH3, substantiated the potential of [11C]4 ([11C]-DMDPA). A proof of concept for the potential of radiolabeled ammonium salts as MPI agents has been demonstrated in a newly developed swine model of permanent partial coronary artery occlusion.SAR studies of 11C-labeled ammonium salts suggest that both lipophilicity and charge density affect the performance of these compounds as MPI probes. In a swine model, the labeled lead successfully visualized the defect regions in the myocardium. The data presented call for the development of fluorine-18 analogues, to increase clinical impact.

    View details for DOI 10.1007/s11307-011-0539-6

    View details for Web of Science ID 000308819300013

    View details for PubMedID 22290562

  • Blood vessels restrain pancreas branching, differentiation and growth DEVELOPMENT Magenheim, J., Ilovich, O., Lazarus, A., Klochendler, A., Ziv, O., Werman, R., Hija, A., Cleaver, O., Mishani, E., Keshet, E., Dor, Y. 2011; 138 (21): 4743-4752

    Abstract

    How organ size and form are controlled during development is a major question in biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here, we report that, surprisingly, non-nutritional signals from blood vessels act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus, the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells.

    View details for DOI 10.1242/dev.066548

    View details for Web of Science ID 000296060100017

    View details for PubMedID 21965615

  • A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways DEVELOPMENT Lazarus, A., Del-Moral, P. M., Ilovich, O., Mishani, E., Warburton, D., Keshet, E. 2011; 138 (11): 2359-2368

    Abstract

    Blood vessels have been shown to play perfusion-independent roles in organogenesis. Here, we examined whether blood vessels determine branching stereotypy of the mouse lung airways in which coordinated branching of epithelial and vascular tubes culminates in their co-alignment. Using different ablative strategies to eliminate the lung vasculature, both in vivo and in lung explants, we show that proximity to the vasculature is indeed essential for patterning airway branching. Remarkably, although epithelial branching per se proceeded at a nearly normal rate, branching stereotypy was dramatically perturbed following vascular ablation. Specifically, branching events requiring a rotation to change the branching plane were selectively affected. This was evidenced by either the complete absence or the shallow angle of their projections, with both events contributing to an overall flat lung morphology. Vascular ablation also led to a high frequency of ectopic branching. Regain of vascularization fully rescued arrested airway branching and restored normal lung size and its three-dimensional architecture. This role of the vasculature is independent of perfusion, flow or blood-borne substances. Inhibition of normal branching resulting from vascular loss could be explained in part by perturbing the unique spatial expression pattern of the key branching mediator FGF10 and by misregulated expression of the branching regulators Shh and sprouty2. Together, these findings uncovered a novel role of the vasculature in organogenesis, namely, determining stereotypy of epithelial branching morphogenesis.

    View details for DOI 10.1242/dev.060723

    View details for Web of Science ID 000290430100020

    View details for PubMedID 21558382

  • Growth-limiting role of endothelial cells in endoderm development DEVELOPMENTAL BIOLOGY Sand, F. W., Hornblad, A., Johansson, J. K., Loren, C., Edsbagge, J., Stahlberg, A., Magenheim, J., Ilovich, O., Mishani, E., Dor, Y., Ahlgren, U., Semb, H. 2011; 352 (2): 267-277

    Abstract

    Endoderm development is dependent on inductive signals from different structures in close vicinity, including the notochord, lateral plate mesoderm and endothelial cells. Recently, we demonstrated that a functional vascular system is necessary for proper pancreas development, and that sphingosine-1-phosphate (S1P) exhibits the traits of a blood vessel-derived molecule involved in early pancreas morphogenesis. To examine whether S1P(1)-signaling plays a more general role in endoderm development, S1P(1)-deficient mice were analyzed. S1P(1) ablation results in compromised growth of several foregut-derived organs, including the stomach, dorsal and ventral pancreas and liver. Within the developing pancreas the reduction in organ size was due to deficient proliferation of Pdx1(+) pancreatic progenitors, whereas endocrine cell differentiation was unaffected. Ablation of endothelial cells in vitro did not mimic the S1P(1) phenotype, instead, increased organ size and hyperbranching were observed. Consistent with a negative role for endothelial cells in endoderm organ expansion, excessive vasculature was discovered in S1P(1)-deficient embryos. Altogether, our results show that endothelial cell hyperplasia negatively influences organ development in several foregut-derived organs.

    View details for DOI 10.1016/j.ydbio.2011.01.026

    View details for Web of Science ID 000289180200008

    View details for PubMedID 21281624

  • Novel and Simple Carbon-11-Labeled Ammonium Salts as PET Agents for Myocardial Perfusion Imaging MOLECULAR IMAGING AND BIOLOGY Ilovich, O., Billauer, H., Dotan, S., Freedman, N. M., Bocher, M., Mishani, E. 2011; 13 (1): 128-139

    Abstract

    Positron emission tomography (PET) has clear advantages over single photon emission computed tomography (SPECT) in the field of myocardial perfusion scintigraphy (MPS); however, there are just a small number of efficient PET tracers available today for MPS. We sought to develop and perform a preliminary biological evaluation of novel carbon-11-labeled ammonium salts as potential MPS PET agents.Three potential tracers were labeled and evaluated via biodistribution in mice and PET imaging in both rats and rabbits, and the results obtained were also compared to agents that are routinely used in the clinical practice.The results designated carbon-11-labeled ammonium salts as having great potential as MPS PET agents. Specifically, carbon-11-labeled trimethyl-phenyl-ammonium iodide ([(11)C]2) and homologues of higher lipophilicity/charge warrant further studies in larger animals and humans such as measurements of myocardial uptake at rest and stress under both normal and pathological coronary flow conditions.

    View details for DOI 10.1007/s11307-010-0336-7

    View details for Web of Science ID 000286395600017

    View details for PubMedID 20480244

  • Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers BIOORGANIC & MEDICINAL CHEMISTRY Ilovich, O., Billauer, H., Dotan, S., Mishani, E. 2010; 18 (2): 612-620

    Abstract

    In a continued effort to find a suitable PET tracer for visualization of angiogenic processes, we explored the 3,4-diarylmaleimide family, known to have high affinity and selectivity towards the VEGFR-TKs. One previously reported agent and three new halogen-containing 3,4-diarylmaleimide derivatives were synthesized. The four maleimide derivatives were evaluated for their affinity and selectivity towards the VEGFRs and exhibited promising results. An automated carbon-11 radiolabeling route with a total synthesis time of 50min successfully labeled the lead compound, resulting in 1.55+/-0.15GBq of tracer with a radiochemical yield of 20+/-2%, 96% radiochemical purity and a SA of 111+/-22GBq/micromol (EOB, n=5). The tracer possessed high stability in in vitro blood stability tests and specific VEGFR-TK binding profiles in intact cell binding experiments. Tracer lipophilicity was evaluated in an n-octanol/phosphate buffer system giving a LogD(7.4) of 1.99+/-0.04. For the in vivo experiments, two animal models were used. The first was a U87 glioma tumor model, frequently reported in the literature and the second, a newly developed 293/KDR tumor model. Both models were validated for VEGFR-2 expression and used in in vivo biodistribution studies. These studies revealed low accumulation and rapid washout of the tracer from tumor tissue. High accumulation of activity in the liver prompted us to examine the tracer's in vitro stability to liver microsomes, revealing low resistance to P450 metabolism. In spite of encouraging in vitro results, the labeled lead tracer failed to accumulate in VEGFR-2 overexpressing tumors. It is possible that poor resistance to P450 metabolism reduces tracer's circulation leading to low tumor accumulation.

    View details for DOI 10.1016/j.bmc.2009.12.004

    View details for Web of Science ID 000273613500014

    View details for PubMedID 20031417

  • Formation of fluorine-18 labeled diaryl ureas - labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents for angiogenesis BIOORGANIC & MEDICINAL CHEMISTRY Ilovich, O., Jacobson, O., Aviv, Y., Litchi, A., Chisin, R., Mishani, E. 2008; 16 (8): 4242-4251

    Abstract

    Urea subunits are common components of various pharmaceuticals' core structure. Since in most cases the design and development of PET biomarkers is based on approved or potential drugs, there is a growing need for a general labeling methodology of urea-containing pharmacophores. As a part of research in the field of molecular imaging of angiogenic processes, we synthesized several highly potent VEGFR-2/PDGFR dual inhibitors as potential PET biomarkers. The structure of these inhibitors is based on the N-phenyl-N'-{4-(4-quinolyloxy)phenyl}urea skeleton. A representative inhibitor was successfully labeled with fluorine-18 by a three-step process. Initially, a two-step radiosynthesis of 4-[(18)F]fluoro-aniline from 1,4-dinitrobenzene (60min, EOB decay corrected yield: 63%) was performed. At the third and final step, the 4-[(18)F]fluoro-aniline synthon reacted for 30min at room temperature with 4-(2-fluoro-4-isocyanato-phenoxy)-6,7-dimethoxy-quinoline to give complete conversion of the labeled synthon to 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-[(18)F]fluoro-phenyl)-urea. The desired labeled product was obtained after total radiosynthesis time of 3h including HPLC purification with 46+/-1% EOB decay corrected radiochemical yield, 99% radiochemical purity, 99% chemical purity, and a specific activity of 400+/-37GBq/mmol (n=5).

    View details for DOI 10.1016/j.bmc.2008.02.081

    View details for Web of Science ID 000255246100004

    View details for PubMedID 18343125

  • 4-(3 'alpha 15 'beta-dihydroxy-5 'beta-estran-17 'beta-yl)furan-2-methyl alcohol: An anti-digoxin agent with a novel mechanism of action JOURNAL OF MEDICINAL CHEMISTRY Deutsch, J., Jang, H. G., Mansur, N., Ilovich, O., Shpolansky, U., Galili, D., Feldman, T., Rosen, H., Lichtstein, D. 2006; 49 (2): 600-606

    Abstract

    The synthesis and some pharmacological properties of 4-(3'alpha-15'beta-dihydroxy-5beta-estran-17'beta-yl)furan-2-methyl alcohol (16) have been described. The compound was synthesized by reacting a synthetic 3alpha- benzyloxy-5beta-estr-15-en-17-one with the ethylene acetal of 4-bromo-2-furancarboxyaldehyde, followed by hydrolysis of the ethylene acetal and reduction of the aldehyde. Despite its resemblance to the structure of cardiac steroids (CS), 16 does not bind to the CS receptor on Na(+),K(+)-ATPase and does not increase the force of contraction of heart muscle. However, 16 inhibited the digoxin-induced increase in the force of contraction and arrhythmias in guinea pig papillary muscle and human atrial appendages. The steroid also inhibited digoxin-induced alteration in endocytosed membrane traffic, indicating a novel mechanism of action.

    View details for DOI 10.1021/jm0505819

    View details for Web of Science ID 000234836200020

    View details for PubMedID 16420045

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