One-Step 18F-Labeling and Preclinical Evaluation of Prostate-Specific Membrane Antigen Trifluoroborate Probes for Cancer Imaging.

Hsiou-Ting Kuo,Jinhe Pan,Zhengxing Zhang,Aron Roxin,François Bénard,Chengcheng Zhang,Alla Pryyma,Zhibo Liu,Kuo-Shyan Lin,David M Perrin,Mathieu L Lepage,Helen Merkens

doi:10.2967/jnumed.118.216598

Abstract

After the identification of the high-affinity glutamate-ureido scaffold, the design of several potent 18F- and 68Ga-labeled tracers has allowed spectacular progress in imaging recurrent prostate cancer by targeting the prostate-specific membrane antigen (PSMA). We evaluated a series of PSMA-targeting probes that are 18F-labeled in a single step for PET imaging of prostate cancer. Methods: We prepared 8 trifluoroborate constructs for prostate cancer imaging, to study the influence of the linker and the trifluoroborate prosthetic on pharmacokinetics and image quality. After 1-step labeling by 19F–18F isotopic exchange, the radiotracers were injected in mice bearing LNCaP xenografts, with or without blocking controls, to assess specific uptake. PET/CT images and biodistribution data were acquired at 1 h after injection and compared with 18F-DCFPyL on the same mouse strain and tumor model. Results: All tracers exhibited nanomolar affinities, were labeled in good radiochemical yields at high molar activities, and exhibited high tumor uptake in LNCaP xenografts with clearance from nontarget organs. Most derivatives with a naphthylalanine linker showed significant gastrointestinal excretion. A radiotracer incorporating this linker with a dual trifluoroborate-glutamate labeling moiety showed high tumor uptake, low background activity, and no liver or gastrointestinal track accumulation. Conclusion: PSMA-targeting probes with trifluoroborate prosthetic groups represent promising candidates for prostate cancer imaging because of facile labeling while affording high tumor uptake values and contrast ratios that are similar to those obtained with 18F-DCFPyL.

Highlights

The prostate-specific membrane antigen (PSMA), a transmembrane metalloenzyme [1], is highly overexpressed in prostate cancer and tumor-associated neovasculature [2]
The diamino acid glutamate-ureido is commonly used for PSMA targeting because of synthetic ease, rapid pharmacokinetics, and high contrast ratios [7]. 68Ga-PSMA-11 is currently the most commonly used radioligand for prostate cancer imaging [8,9]
We report the synthesis, radiolabeling, and PET imaging of radiotracers based on the glutamate-ureido-lysine scaffold bearing RBF32 radioprosthetic groups

Summary

Introduction

The prostate-specific membrane antigen (PSMA), a transmembrane metalloenzyme [1], is highly overexpressed in prostate cancer and tumor-associated neovasculature [2]. 18F has several advantages, including a longer half-life (109.8 min); higher spatial resolution than 68Ga due to its short positron range; and on-demand, scalable production of 18F-fluoride ions up to a few hundred gigabecquerels [11] To this effect, 18F-labeled PSMA-targeting radiotracers such as 18F-DCFPyL [12] and 18F-PSMA-1007 [13] have been introduced in clinical studies. We report the synthesis, radiolabeling, and PET imaging of radiotracers based on the glutamate-ureido-lysine scaffold bearing RBF32 radioprosthetic groups (compounds 1–8, Fig. 1). We measured their binding affinity toward PSMA and LogD7.4 values and acquired PET images and ex vivo biodistribution data in mice bearing PSMA-expressing LNCaP prostate cancer xenografts. These results were compared with those of 18F-DCFPyL, a clinically emergent 18F-labeled tracer for prostate cancer imaging

Methods

Results

Discussion

Conclusion