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

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 [ 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.

Diagnostic and Therapeutic Radiopharmaceuticals: A “Hot” Topic

“…Ex vivo aortic autoradiography and competition studies revealed that [ 18 F]20 (Figure 3) specifically binds to MMP-13 within atherosclerotic plaques and localizes to lipid-rich regions. 37 GPR119 is a G protein-coupled receptor, highly expressed in the pancreas, that regulates secretion of insulin and incretins, and is a target for drug development to treat diabetes. Measuring GPR119 levels in vivo could significantly advance 3+ , demonstrating quantitative radiochemical yields (RCYs) within 10 min at ambient temperature and achieving notably high molar activities.…”

“…The manuscript by Rotstein et al reported the synthesis and preclinical evaluations of selective matrix metallo­proteinase-13 (MMP-13) PET radio­tracers for the early detection of unstable plaques that are risk factors for acute ischemia. Ex vivo aortic auto­radiography and competition studies revealed that [ 18 F] 20 (Figure ) specifically binds to MMP-13 within athero­sclerotic plaques and localizes to lipid-rich regions …”