Synthesis and Evaluation of [ 11 C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis.
Uzair S IsmailaniAriel BuchlerNicole MacMullinFaduma AbdirahmanMyriam AdiBenjamin H RotsteinPublished in: Molecular pharmaceutics (2023)
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 [ 11 C]MCC950 with no-carrier-added [ 11 C]CO 2 fixation chemistry using an iminophosphorane precursor (RCY 45 ± 4%, >99% RCP, 27 ± 2 GBq/μmol, 23 ± 3 min, n = 6) and determined its distribution both in vivo and ex vivo in C57BL/6 and atherogenic ApoE -/- 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 in vivo stability of [ 11 C]MCC950 (94% intact). Ex vivo autoradiography performed on excised aortas revealed heterogeneous uptake in atherosclerotic plaques of ApoE -/- mice in comparison to C57BL/6 controls (48 ± 17 %ID/m 2 vs 18 ± 8 %ID/m 2 , p = 0.002, n = 4-5). Treatment of ApoE -/- 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, p = 0.04, n = 4-6) and in aortic lesions (48 ± 17 %ID/m 2 vs 104 ± 15 %ID/m 2 , p = 0.0002, n = 5) by 108% and 117%, respectively, without significantly increasing plasma free fraction ( f p , 1.3 ± 0.4% vs 1.7 ± 0.8%, n = 2). These results suggest that [ 11 C]MCC950 uptake demonstrates specific binding and may prove useful for in vivo NLRP3 imaging in atherosclerosis.
Keyphrases
- pet imaging
- nlrp inflammasome
- positron emission tomography
- pulmonary arterial hypertension
- computed tomography
- cognitive decline
- high fat diet induced
- cardiovascular disease
- pulmonary artery
- high fat diet
- high resolution
- pulmonary hypertension
- minimally invasive
- left ventricular
- multiple sclerosis
- heart failure
- escherichia coli
- cell proliferation
- single cell
- insulin resistance
- aortic valve
- type diabetes
- transcription factor
- high dose
- machine learning
- big data
- wild type
- atrial fibrillation
- dna binding
- clinical evaluation