Radiosynthesis and Preclinical Evaluation of ¹¹C-VA426, a Cyclooxygenase-2 Selective Ligand

Abstract

Cyclooxygenase-2 (COX-2) is involved in the inflammatory response, and its recurrent overexpression in cancers as well as in neurodegenerative disorders has made it an important target for therapy. For this reason, noninvasive imaging of COX-2 expression may represent an important diagnostic tool. In this work, a COX-2 inhibitor analogue, VA426 [1-(4-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-5-(4-(methylsulfonil)phenyl)-1H-pyrrole], was synthesized and radiolabelled with the 11C radioisotope. The ex vivo biodistribution profile of 11C-VA426 was evaluated in the brain and periphery of healthy rats and mice and in brain and periphery of inflammation models, based on the administration of LPS. 11C-VA426 synthesis with the tBuOK base showed optimal radiochemical yield (15 ± 2%) based on triflate activity, molar activity (range 37–148 GBq/μmol), and radiochemical purity (>95%). Ex vivo biodistribution studies showed a fast uptake of radioactivity but a rapid washout, except in regions expressing COX-2 (lungs, liver, and kidney) both in rats and in mice, with maximum values at 30 and 10 minutes p.i., respectively. LPS administration did not show significant effect on radioactivity accumulation. Celecoxib competition experiments performed in rats and mice treated with LPS produced a general target unrelated reduction of radioactivity concentration in all peripheral tissues and brain areas examined. Finally, in agreement with the negative results obtained from biodistribution experiments, radiometabolites analysis revealed that 11C-VA426 is highly unstable in vivo. This study indicates that the compound 11C-VA426 is not currently suitable to be used as radiopharmaceutical for PET imaging. This family of compounds needs further implementation in order to improve in vivo stability.

Cyclooxygenases as Potential PET Imaging Biomarkers to Explore Neuroinflammation in Dementia

“…1), and 11 C-arachidonic acid is the only radiotracer mentioned in these reviews that has moved to human studies (28,29). Both these early radioligands and more recently developed ones (30)(31)(32)(33)(34)(35) were primarily unsuccessful because of high nonspecific binding. However, in some cases, radiodefluorination (36,37), rapid metabolism (36), and poor brain entry (38)(39)(40) were also reasons for failure.…”

Fluorine-18 Labelled Radioligands for PET Imaging of Cyclooxygenase-2

“…There has also been significant progress in the development of COX-2-targeting radioligands for imaging inflammation, cancer, and neurological disorders [54][55][56][57]. Over the last decades, a variety of radionuclide-based imaging agents have been developed by the incorporation of radioisotopes such as 11 C, 18 F, 99m Tc, 123 I, and 125 I into NSAIDs and related compounds [55,56,[58][59][60][61][62][63][64][65][66][67][68][69][70][71]. Selected examples of PET radioligands for COX-2 imaging are presented in Figure 3 Molecules 2022, 27, x FOR PEER REVIEW 3 of 20…”

“…There has also been significant progress in the development of COX-2-targeting radioligands for imaging inflammation, cancer, and neurological disorders [54][55][56][57]. Over the last decades, a variety of radionuclide-based imaging agents have been developed by the incorporation of radioisotopes such as 11 C, 18 F, 99m Tc, 123 I, and 125 I into NSAIDs and related compounds [55,56,[58][59][60][61][62][63][64][65][66][67][68][69][70][71]. Selected examples of PET radioligands for COX-2 imaging are presented in Figure 3 A major focus involves 18 F-labeled radioligands, due to their favourable half-life (t1/2 = 109.8 min), ease of production, the availability of a variety of radiofluorination methods, and better imaging characteristics of the short-lived positron emitter 18 F. This review article primarily covers 18 F-labeled radioligands reported in the last decade for targeting COX-2.…”