Buchler, ArielIsmailani, Uzair SMacMullin, NicoleAbdirahman, FadumaAdi, MyriamBi, ChristinaJany, CatherineKeillor, Jeffrey WRotstein, Benjamin H2023-05-312023J. Med. Chem. 2023, 66(10), 6682-66960022-2623https://doi.org/10.1021/acs.jmedchem.2c02107https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c02107http://hdl.handle.net/10393/45020https://doi.org/10.20381/ruor-29226Matrix metalloproteinase-13 (MMP-13) plays a critical role in the progression of unstable atherosclerosis. A series of highly potent and selective MMP-13 inhibitors were synthesized around a quinazoline-2-carboxamide scaffold to facilitate radiolabeling with fluorine-18 or carbon-11 positron-emitting nuclides and visualization of atherosclerotic plaques. In vitro enzyme inhibition assays identified three compounds as promising radiotracer candidates. Efficient automated radiosyntheses provided [11C]5b, [11C]5f, and [18F]5j and enabled pharmacokinetic characterization in atherosclerotic mice. The radiotracers displayed substantial differences in their distribution and excretion. Most favorably for vascular imaging, [18F]5j exhibited low uptake in metabolic organs with minimal retention of myocardial radioactivity, substantial renal clearance, and high metabolic stability in plasma. Ex vivo aortic autoradiography and competition studies revealed that [18F]5j specifically binds to MMP-13 within atherosclerotic plaques and localizes to lipid-rich regions. This study demonstrates the utility of the quinazoline-2-carboxamide scaffold for MMP-13 selective positron emission tomography (PET) radiotracer development and identifies [18F]5j for imaging atherosclerosis.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/MiceAnimalsMatrix Metalloproteinase 13Positron-Emission TomographyAortaRadiopharmaceuticalsPlaque, AtheroscleroticAtherosclerosisArticle10.1021/acs.jmedchem.2c02107