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 cancer

Prostate. 2020 Dec;80(16):1383-1393. doi: 10.1002/pros.24062. Epub 2020 Sep 22.

Abstract

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 (Ki ). 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.

Keywords: PET radiopharmaceuticals; PSMA; click chemistry; rapid renal clearance; tumor-to-background ratio.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Fluorine Radioisotopes / pharmacokinetics*
  • Humans
  • Ligands
  • Male
  • Mice
  • Positron-Emission Tomography / methods*
  • Prostate / diagnostic imaging*
  • Prostate-Specific Antigen*
  • Prostatic Neoplasms / diagnostic imaging*
  • Radiopharmaceuticals / pharmacokinetics*

Substances

  • Fluorine Radioisotopes
  • Ligands
  • Radiopharmaceuticals
  • Prostate-Specific Antigen