Design, synthesis and evaluation of 18F-labeled bradykinin B1 receptor-targeting small molecules for PET imaging

Two fluorine-18 (F-18) labeled bradykinin B1 receptor (B1R)-targeting small molecules, F-18-Z02035 and F-18-Z02165, were synthesized and evaluated for imaging with positron emission tomography (PET). Z02035 and Z02165 were derived from potent antagonists, and showed high binding affinity (0.93 +/- 0.44 and 2.80 +/- 0.50 nM, respectively) to B1R. F-18-Z02035 and F-18-Z02165 were prepared by coupling 2-[F-18] fluoroethyl tosylate with their respective precursors, and were obtained in 10 +/- 5 (n = 4) and 22 +/- 14% (n = 3), respectively, decay-corrected radiochemical yield with >99% radiochemical purity. F-18-Z02035 and F-18- Z02165 exhibited moderate lipophilicity (LogD(7.4) = 1.10 and 0.59, respectively), and were stable in mouse plasma. PET imaging and biodistribution studies in mice showed that both tracers enabled visualization of the B1R-positive HEK293T::hB1R tumor xenografts with better contrast than control B1R-negative HEK293T tumors. Our data indicate that small molecule antagonists can be used as pharmacophores for the design of B1R-targeting PET tracers. (C) 2016 Elsevier Ltd. All rights reserved.