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

Abstract

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.

Keywords: PSMA; imaging; positron emission tomography; preclinical model; prostate carcinoma; radiofluorination.

© 2019 by the Society of Nuclear Medicine and Molecular Imaging.

Figures

FIGURE 1.

Previously known PSMA-specific PET tracers (68Ga-1,18F-2, and 18F-3) and emerging probes (18F-JK-4-11) investigated in this study.

FIGURE 2.

Preparation of 18F-2 and 18F-4-10. TEABC = tetraethylammonium bicarbonate.

FIGURE 3.

Tracer uptake in LNCaP C4-2 cells in relation to 18F-DCFPyL. 18F-DCFPyL uptake after 2 h was normalized to 100%. Only 18F-JK-PSMA-7 shows higher uptake than 18F-DCFPyL. *Significantly different from 18F-DCFPyL at same time point. F7,38 = 1,136; P < 0.0001 for factor “tracer,” post hoc P < 0.05. #Significantly higher than 2-h uptake of same tracer. F1,38 = 6,981; P < 0.0001 for factor “time,” post hoc P < 0.05.

FIGURE 4.

TBR of PSMA tracers. (A) Sagittal section of PSMA image with SCG and background (Bg) volumes of interest. (B) Graph showing that TBR (SCG/Bg) 60–120 min after injection did not significantly differ among groups (F4,10 = 2.95, P = 0.0756). (C) TBR analyzed for four 30-min frames. *TBE significantly higher for 18F-JK-PSMA-7 than for 68Ga-PSMA-11 (F4,40 = 5.97, P = 0.0102, for factor “tracer,” post hoc P < 0.05). #TBR significantly higher for 18F-JK-PSMA-7 than for 18F-JK-PSMA-8 or 68Ga-PSMA-11 (P < 0.05). TBR of 18F-JK-PSMA-7 and 18F-PSMA-1007 increased significantly over time (F3,30 = 9.12, P = 0.0002, for factor “frame”). †For 18F-JK-PSMA-7, frame 4 was significantly different from frames 1 and 2 (P < 0.05). ‡For 18F-PSMA-1007, frame 4 was significantly different from frame 1 (P < 0.05).

FIGURE 5.

Acutance (measured for SCG) using different PSMA tracers. (A) Profile plot of 1-pixel profile (Pr in inset) through SCG center. Peak against adjacent background (max) and FWHM were measured. (B) Ratio max/FWHM roughly represents slope of profile plot and reflects acutance. *18F-JK-PSMA-7 and 18F-PSMA-1007 show significantly higher acutance than 18F-DCFPyL, 18F-JK-PSMA-8, or 68Ga-PSMA-11 (F4,10 = 12.77, P = 0.0006; post hoc P < 0.05). %ID = percentage injected dose.

FIGURE 6.

Resolution of images acquired with different tracers. (A) Profile plot of 1-pixel profile (Pr in inset) through apical pair of DRG. Peak against adjacent background (max) and FWHM were measured for each ganglion. P2–P1 was distance between peaks. (B) Formula R = 2(P2 − P1)/1.7(FWHM1 + FWHM2) yields image resolution. *Image resolution was significantly higher for 18F-JK-PSMA-7 than for 18F-JK-PSMA-8 (F4,10 = 3.80, P = 0.0396; post hoc P < 0.05).

FIGURE 7.

18F-JK-PSMA-7 scan in patient with relapsed PCa. This 64-y-old patient had serum prostate-specific antigen level of 130 ng/mL. Scan was started 233 min after injection of 384 MBq of 18F-JK-PSMA-7. (Left) Maximum-intensity projection of PET image. (Right) PET/CT images at transverse levels indicated by blue lines.