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

Two fluorine-18 (18F) labeled bradykinin B1 receptor (B1R)-targeting small molecules, 18F-Z02035 and 18F-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. 18F-Z02035 and 18F-Z02165 were prepared by coupling 2-[18F]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. 18F-Z02035 and 18F-Z02165 exhibited moderate lipophilicity (Log D7.4 = 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.

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