title: Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers.
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.
authors.affiliation: Cyclotron/Radiochemistry Unit, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel.
authors.forename: Ohad
authors.initials: O
authors.lastname: Ilovich
authors.forename: Hana
authors.initials: H
authors.lastname: Billauer
authors.forename: Sharon
authors.initials: S
authors.lastname: Dotan
authors.forename: Eyal
authors.initials: E
authors.lastname: Mishani
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D008297:Male; D008301:Maleimides / Q000032:analysis* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D049268:Positron-Emission Tomography / Q000379:methods*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D043925:Angiogenesis Inducing Agents; D014408:Biomarkers, Tumor; D008301:Maleimides; D040262:Receptors, Vascular Endothelial Growth Factor