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

Abstract

After the identification of the high-affinity glutamate-ureido scaffold, the design of several potent 18 F- and 68 Ga-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 18 F-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 19 F– 18 F 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 18 F-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 18 F-DCFPyL.

Toward 18F‐Labeled Theranostics: A Single Agent that Can Be Labeled with 18F, 64Cu, or 177Lu

“…As such, the data from ( 18 F/free ) at 2 h p.i. show tumor uptake values comparable to those obtained with 18 F‐DCFPyL, the emerging clinical standard for PSMA imaging . Significantly, the tumor/muscle ratio of 160 (see the Supporting Information) is higher than that obtained with 18 F‐DCFPyL .…”

“…To begin, the use of a metal‐free DOTA moiety to favor renal uptake over hepatobiliary uptake in the context of an 18 F‐labeled tracer represents a recent application in PET tracer design that has only been used once (by us), yet was never investigated with regard to applications in (radio)metalation . Here too, regarding PSMA imaging, we note that the addition of DOTA greatly diminishes hepatobiliary uptake and thus enhances tumor/liver and tumor/intestine ratios compared to a similar EUK–AMBF 3 conjugate lacking the DOTA that we reported recently . As such, the data from ( 18 F/free ) at 2 h p.i.…”

“…[17] Here too, regarding PSMA imaging, we note that the addition of DOTA greatly diminishes hepatobiliary uptake and thus en- hances tumor/liver and tumor/intestine ratios compared to a similar EUK-AMBF 3 conjugate lacking the DOTA that we reported recently. [25] As such, the data from ( 18 F/free) at 2 h p.i. show tumor uptake values comparable to those obtained with 18 F-DCFPyL, the emerging clinical standard for PSMA imaging.…”

“…show tumor uptake values comparable to those obtained with 18 F-DCFPyL, the emerging clinical standard for PSMA imaging. [25] Significantly, the tumor/muscle ratio of 160 (see the Supporting Information) is higher than that obtained with 18 F-DCFPyL. [26] Thus, irrespective of any theranostic applications to be gleaned with radiometals, DOTA-AMBF 3 -PSMA, labeled as ( 18 F/free), represents a novel and promising preclinical lead for imaging PCa with 18 F-PET.…”

High-Efficiency Production of Radiopharmaceuticals via Droplet Radiochemistry: A Review of Recent Progress

“…28 Notably, the radiochemical yield was similar among all of these approaches. Microdroplet IEX approaches could likely be extended to other tracers based on trifluoroborates, 70,71 aryl fluorosulfate 72 and silicon-fluoride 73,74 with the same benefits.…”