Synthesis and Evaluation of [<sup>11</sup>C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".