Synthesis and Evaluation of [C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis.

Overexpression of the NLRP3 inflammasome has been attributed to the progressive worsening of a multitude of cardiovascular inflammatory diseases such as myocardial infarction, pulmonary arterial hypertension, and atherosclerosis. The recently discovered potent and selective NLRP3 inhibitor MCC950 has shown promise in hindering disease progression, but NLRP3-selective cardiovascular positron emission tomography (PET) imaging has not yet been demonstrated. We synthesized [C]MCC950 with no-carrier-added [C]CO fixation chemistry using an iminophosphorane precursor (RCY 45 ± 4%, >99% RCP, 27 ± 2 GBq/μmol, 23 ± 3 min, = 6) and determined its distribution both and in C57BL/6 and atherogenic mice. Small animal PET imaging was performed in both strains following intravenous administration via the lateral tail vein and revealed considerable uptake in the liver that stabilized by 20 min (7-8.5 SUV), coincident with secondary renal excretion. Plasma metabolite analysis uncovered excellent stability of [C]MCC950 (94% intact). autoradiography performed on excised aortas revealed heterogeneous uptake in atherosclerotic plaques of mice in comparison to C57BL/6 controls (48 ± 17 %ID/m vs 18 ± 8 %ID/m, = 0.002, = 4-5). Treatment of mice with nonradioactive MCC950 (5 mg/kg, iv) 10 min prior to radiotracer administration increased uptake in the intestine (5.3 ± 1.8 %ID/g vs 11.0 ± 3.7 %ID/g, = 0.04, = 4-6) and in aortic lesions (48 ± 17 %ID/m vs 104 ± 15 %ID/m, = 0.0002, = 5) by 108% and 117%, respectively, without significantly increasing plasma free fraction (, 1.3 ± 0.4% vs 1.7 ± 0.8%, = 2). These results suggest that [C]MCC950 uptake demonstrates specific binding and may prove useful for NLRP3 imaging in atherosclerosis.