Impact of structural alterations on the radiopharmacological profile of 18 F-labeled pyrimidines as cyclooxygenase-2 (COX-2) imaging agents.

Research paper by Ole O Tietz, Alison A Marshall, Cody C Bergman, Melinda M Wuest, Frank F Wuest

Indexed on: 26 May '18Published on: 26 May '18Published in: Nuclear Medicine and Biology


Non-invasive imaging of COX-2 in cancer represents a powerful tool for assessing COX-2-mediated effects on chemoprevention and radiosensitization using potent and selective COX-2 inhibitors as an emerging class of anticancer drugs. Careful assessment of the pharmacokinetic profile of radiolabeled COX-2 inhibitors is of crucial importance for the development of suitable radiotracers for COX-2 imaging in vivo. The delicate balance between the selection of typical COX-2 pharmacophores and the resulting physicochemical characteristics of the COX-2 inhibitor represents a formidable challenge for the search of radiolabeled COX-2 imaging agents. Several pyrimidine-based COX-2 inhibitors demonstrated favorable in vitro and in vivo COX-2 imaging properties in various COX-2 expressing cancer cell lines. Here, we describe a comparative radiopharmacological study of three F-labeled COX-2 inhibitors based on a pyrimidine scaffold. The objective of this study was to investigate how subtle structural alterations influence the pharmacokinetic profile of lead compound [F]1a ([F]Pyricoxib) to afford F-labeled pyrimidine-based COX-2 inhibitors with improved COX-2 imaging properties in vivo. Radiosynthesis of radiotracers was accomplished through reaction with 4-[F]fluorobenzyl amine on a methyl-sulfone labeling precursor ([F]1a and [F]2a) or late-stage radiofluorination using a iodyl-containing labeling precursor ([F]3a). Radiopharmacological profile of F-labeled pyrimidine-based COX-2 inhibitors [F]1a, [F]2a and [F]3a was studied in COX-2-expressing human HCA-7 colorectal cancer cell line, including cellular uptake studies in HCA-7 cells and dynamic PET imaging studies in HCA-7 xenografts. Cellular uptake of radiotracers [F]2a and [F]3a in HCA-7 cells was 450% and 300% radioactivity/mg protein, respectively, after 90 min incubation, compared to 600% radioactivity/mg protein for radiotracer [F]1a. Dynamic PET imaging studies revealed a tumor SUV of 0.53 ([F]2a) and 0.54 ([F]3a) after 60 min p.i. with a tumor-to-muscle ratio of ~1. Tumor SUV for [F]1a (60 min p.i.) was 0.76 and a tumor-to-muscle ratio of ~1.5. Pyricoxib analogues [F]2a and [F]3a showed distinct pharmacokinetic profiles in comparison to lead compound [F]1a with a significantly improved lung clearance pattern. Replacing the 4-[F]fluorobenzyl amine motif in radiotracer [F]1a with a 4-[F]fluorobenzyl alcohol motif in radiotracer [F]3a resulted in re-routing of the metabolic pathway as demonstrated by a more rapid liver clearance and higher initial kidney uptake and more rapid kidney clearance compared to radiotracers [F]1a and [F]2a. Moreover, radiotracer [F]3a displayed favorable rapid brain uptake and retention. The radiopharmacological profile of three F-labeled COX-2 inhibitors based on a pyrimidine scaffold were evaluated in COX-2 expressing human colorectal cancer cell line HCA-7 and HCA-7 xenografts in mice. Despite the overall structural similarity and comparable COX-2 inhibitory potency of all three radiotracers, subtle structural alterations led to significantly different in vitro and in vivo metabolic profiles. Among all tested pyrimidine-based F-labeled COX-2 inhibitors, lead compound [F]1a remains the most suitable radiotracer for assessing COX-2 expression in vivo. Radiotracer [F]3a showed significantly improved first pass pulmonary passage in comparison to radiotracer [F]1a and might represents a promising lead compound for the development of radiotracers for PET imaging of COX-2 in neuroinflammation. Copyright © 2018 Elsevier Inc. All rights reserved.