[18F]Fluoroethyl Triazole Substituted PSMA Inhibitor Exhibiting Rapid Normal Organ Clearance

Prostate-specific membrane antigen (PSMA) is overexpressed in the epithelium of prostate cancer and nonprostate solid tumor neovasculature. PSMA is increasingly utilized as a target for cancer imaging and therapy. Here, we report the synthesis and in vivo biodistribution of a low-molecular-weight PSMA-based imaging agent, 2-[3-(1-carboxy-5-{3- [1(2-[F-18]fluoroethyl)-1H-1,2,3-triazol-yl]propanamido}pentyl)ureido] pentanedioic acid ([F-18]YC-88), containing an [F-18]fluoroethyl triazole moiety. [F-18]YC-88 was synthesized from 2-[F-18]fluoroethyl azide and the corresponding alkyne precursor in two steps using either a one- or two-pot procedure. Biodistribution and positron emission tomography (PET) imaging were performed in immunocompromised mice using isogenic PSMA(+) PC3 PIP and PSMA(-) PC3 flu xenografts. YC-88 exhibited high affinity for PSMA as evidenced by a K-i value of 12.9 nM. The non-decay corrected radiochemical yields of [F-18]YC-88 averaged 14 +/- 1% (n = 5). Specific radioactivities ranged from 320 to 2,460 Ci/mmol (12-91 GBq/ctmol) with an average of 940 Ci/mmol (35 GBq/mu mol, n = 5). In an immunocompromised mouse model, [F-18]YC-88 clearly delineated PSMA(+) PC3 PIP prostate tumor xenografts on imaging with PET. At 1 h postinjection, 47.58 +/- 5.19% injected dose per gram of tissue (% ID/g) was evident within the PSMA(+) PC3 PIP tumor, with a ratio of 170:1 of uptake within PSMA(+) PC3 PIP to PSMA(-) PC3 flu tumor placed in the opposite flank. The tumor-to-kidney ratio at 2 h postinjection was 4:1. At or after 30 min postinjection, minimal nontarget tissue uptake of [F-18]YC-88 was observed. Compared to [F-18]DCFPyL, which is currently in clinical trials, the uptake of [F-18]YC-88 within the kidney, liver, and spleen was significantly lower at all time-points studied. At 30 min and 1 h postinjection, salivary gland uptake of [F-18]YC-88 was significantly less than that of [F-18]DCFPyL. [F-18]YC-88 is a new PSMA-targeted PET agent synthesized utilizing click chemistry that demonstrates high PSMA 4 tumor uptake in a xenograft model. Because of its low uptake in the kidney, rapid clearance from nontarget organs, and relatively simple one-pot, two-step radiosynthesis, [F-18]YC-88 is a viable new PET radiotracer for imaging PSMA-expressing lesions.