18 F-labeled 1,2,3-triazole-linked Glu-urea-Lys-based PSMA ligands have good pharmacokinetic properties for positron emission tomography imaging of prostate cance.

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 F-18-labeling was achieved in a two-step synthesis consisting of [F-18]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-125]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [F-18]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, compound6fhaving a pyridine moiety showed a high binding affinity of 6.51 +/- 0.19 nM (K-i).F-18-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [F-18]6chad the lowest logPof -2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [F-18]6c, [F-18]6f, and [F-18]6i. Additional microPET/CT experiments of [F-18]6cand [F-18]6fwere performed using PSMA+ PC3-PIP and PSMA- PC3-flu cell-bearing mice. [F-18]6cwas 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-18]6cusing OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 x 10(-3) mSv/MBq. Conclusions [F-18]6cshowed 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.