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  2. Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis

Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis

  • J Med Chem. 2023 May 25;66(10):6682-6696. doi: 10.1021/acs.jmedchem.2c02107.
Ariel Buchler 1 2 Uzair S Ismailani 2 3 Nicole MacMullin 2 Faduma Abdirahman 1 2 Myriam Adi 1 2 Christina Bi 1 2 Catherine Jany 2 Jeffrey W Keillor 1 Benjamin H Rotstein 1 2 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario K1N 9B4, Canada.
  • 2 University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
  • 3 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Abstract

Matrix 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.

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