18F-labeled small molecule inhibitors of prostate specific membrane antigen (PSMA) for PET imaging of prostate cancer

1721 Objectives Over-expression of PSMA in prostate cancer makes it an attractive target for imaging localized and metastatic disease. Our previous success in developing 123I and 99mTc labeled inhibitors of PSMA for SPECT has lead us to evaluate a series of structurally related fluorine containing compounds as radioligands for PET. Methods MIP-1500, (S)-2-(3-((S)-1-carboxy-5-(3-(3-fluoro-4-nitro-phenyl)ureido)pentyl)-ureido)pentanedioic acid and the corresponding 3,4-difluoro-phenyl analog (MIP-1499) were prepared from a common intermediate. Competitive binding on LNCaP cells against 123I-MIP-1072([123I]-(S)-2-(3-((S)-1-carboxy-5-((4-iodobenzyl)amino)pentyl)ureido)pentanedioic acid) was performed. MIP-1500 was radiolabeled using [18F]NaF/kryptofix in DMSO at 100°C/20 min. 18F-MIP-1500 was isolated by C18 SPE using water/ethanol. RCY and RCP were determined using RP C18 HPLC. Results MIP-1499/1500 were synthesized by the reaction of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate with the respective 3-fluoro-4-nitro or 3,4-difluoro phenylisocyanate followed by deprotection and purification by RP C18 HPLC. MIP-1499 and MIP-1500 exhibited high affinity for PSMA in LNCaP cells with IC50values of 12 and 8 nM, respectively. Radiochemical yields of 18F-MIP-1500 ranged from 10-40% at EOS (n =10). The retention time of the labeled product was identical to the precursor, MIP-1500. Non-optimized specific activity was 250 Ci/mmol. Conclusions MIP-1499 and MIP-1500 bind with high affinity to PSMA. The radiolabeling process resulted in 18F-MIP-1500 in good RCY and RCP. 18F-labeling was the result of an isotopic exchange reaction and not due to displacement of nitro group of the precursor. 18F-MIP-1500 is currently being investigated preclinically for the potential use in the imaging of prostate cancer