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-[¹⁸F]fluoroethyl)-1H-1,2,3-triazol-yl]propanamido}pentyl)ureido]pentanedioic acid ([¹⁸F]YC-88), containing an [¹⁸F]fluoroethyl triazole moiety. [¹⁸F]YC-88 was synthesized from 2-[¹⁸F]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 [¹⁸F]YC-88 averaged 14 ± 1% (n = 5). Specific radioactivities ranged from 320 to 2,460 Ci/mmol (12-91 GBq/μmol) with an average of 940 Ci/mmol (35 GBq/μmol, n = 5). In an immunocompromised mouse model, [¹⁸F]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 [¹⁸F]YC-88 was observed. Compared to [¹⁸F]DCFPyL, which is currently in clinical trials, the uptake of [¹⁸F]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 [¹⁸F]YC-88 was significantly less than that of [¹⁸F]DCFPyL. [¹⁸F]YC-88 is a new PSMA-targeted PET agent synthesized utilizing click chemistry that demonstrates high PSMA⁺ 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, [¹⁸F]YC-88 is a viable new PET radiotracer for imaging PSMA-expressing lesions.