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Background: 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. Method: 18 F-labeling was achieved in a two-step synthesis consisting of [ 18 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. [ 125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [ 18 F] DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. Results: 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 i). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [ 18 F]6c had the lowest log P of −2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [ 18 F]6c, [ 18 F]6f, and [ 18 F]6i. Additional microPET/CT experiments of [ 18 F]6c and [ 18 F]6f were performed using PSMA+ PC3-PIP and PSMA− PC3-flu cell-bearing mice. [ 18 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 [ 18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10 −3 mSv/MBq. Conclusions: [ 18 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.

Background: This study compared the effects of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) as 64Cu-chelating agents in newly developed prostate-specific membrane antigen (PSMA) target compounds, 64Cu-cudotadipep and 64Cu-cunotadipep, on pharmacokinetics. Methods: The in vitro stability of the chelators was evaluated using human and mouse serum. In vitro PSMA-binding affinity and cell uptake were compared using human 22Rv1 cells. To evaluate specific PSMA-expressing tumor-targeting efficiency, micro-positron emission tomography (mcroPET)/computed tomography (CT) and biodistribution analysis were performed using PSMA+ PC3-PIP and PSMA− PC3-flu tumor xenografts. Results: The serum stability of DOTA- or NOTA-conjugated 64Cu-cudotadipep and 64Cu-cunotadipep was >97%. The Ki value of the NOTA derivative, cunotadipep, in the in vitro affinity binding analysis was higher (2.17 ± 0.25 nM) than that of the DOTA derivative, cudotadipep (6.75 ± 0.42 nM). The cunotadipep exhibited a higher cellular uptake (6.02 ± 0.05%/1 × 106 cells) compared with the cudotadipep (2.93 ± 0.06%/1 × 106 cells). In the biodistribution analysis and microPET/CT imaging, the 64Cu-labeled NOTA derivative, 64Cu-cunotadipep, demonstrated a greater tumor uptake and lower liver uptake than the DOTA derivative. Conclusions: This study indicates that the PSMA-targeted 64Cu-cunotadipep can be applied in clinical practice owing to its high diagnostic power for prostate cancer.