Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis.
Ariel BuchlerUzair S IsmailaniNicole MacMullinFaduma AbdirahmanMyriam AdiChristina BiCatherine JanyJeffrey W KeillorBenjamin H RotsteinPublished in: Journal of medicinal chemistry (2023)
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 [ 11 C]5b , [ 11 C]5f , and [ 18 F]5j and enabled pharmacokinetic characterization in atherosclerotic mice. The radiotracers displayed substantial differences in their distribution and excretion. Most favorably for vascular imaging, [ 18 F]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 [ 18 F]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 [ 18 F]5j for imaging atherosclerosis.
Keyphrases
- positron emission tomography
- pet imaging
- computed tomography
- high resolution
- pet ct
- cardiovascular disease
- cell migration
- high throughput
- heart failure
- pulmonary artery
- adipose tissue
- gene expression
- fluorescence imaging
- case control
- pulmonary arterial hypertension
- coronary artery
- genome wide
- deep learning
- insulin resistance
- tissue engineering
- dna methylation