Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library.
F-labeling was achieved in a two-step synthesis consisting of [ F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA- PC3-flu cells and 22RV1 cells. [ I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [ F]DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software.
Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (K ). F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [ F]6c had the lowest log P of -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [ F]6c, [ F]6f, and [ F]6i. Additional microPET/CT experiments of [ F]6c and [ F]6f were performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [ F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [ F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10  mSv/MBq.
[ F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

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