Discovery of ¹⁸F-JK-PSMA-7, a PET Probe for the Detection of Small PSMA-Positive Lesions

Prostate-specific membrane antigen (PSMA), expressed by most prostate carcinomas (PCa), is a promising target for PCa imaging. The application of PSMA-specific ¹⁸F-labeled PET probes such as ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007 considerably improved the accuracy of PCa tumor detection. However, there remains a need for further improvements in sensitivity and specificity. The aim of this study was the development of highly selective and specific PSMA probes with enhanced imaging properties, in comparison with ¹⁸F-DCFPyL, ¹⁸F-PSMA-1007, and ⁶⁸Ga-PSMA-11. Methods: Eight novel ¹⁸F-labeled PSMA ligands were prepared. Their cellular uptake in PSMA-positive LNCaP C4-2 and PSMA-negative PC-3 cells was compared with that of ¹⁸F-DCFPyL. The most promising candidates were additionally evaluated by small-animal PET in healthy rats using PSMA-positive peripheral ganglia as a model for small PCa lesions. PET images of the ligand with the best outcome, ¹⁸F-JK-PSMA-7, were compared with those of ¹⁸F-DCFPyL, ¹⁸F-PSMA-1007, and ⁶⁸Ga-PSMA-11 with respect to key image-quality parameters for the time frame 60-120 min. Results: Compared with ¹⁸F-DCFPyL, ¹⁸F-JK-PSMA-7 demonstrated increased PSMA-specific cellular uptake. Although target-to-background ratios of ¹⁸F-DCFPyL and ¹⁸F-PSMA-1007 were comparable, this parameter was higher for ¹⁸F-JK-PSMA-7 and lower for ⁶⁸Ga-PSMA-11. Image acutance was significantly higher for ¹⁸F-JK-PSMA-7 and ¹⁸F-PSMA-1007 than for ¹⁸F-DCFPyL and ⁶⁸Ga-PSMA-11. Image resolution was similar for all 4 tracers. ¹⁸F-PSMA-1007 demonstrated significantly higher blood protein binding and bone uptake than the other tracers. Conclusion:¹⁸F-JK-PSMA-7 is a promising candidate for high-quality visualization of small PSMA-positive lesions. Excellent preclinical imaging properties justify further preclinical and clinical studies of this tracer.