Synthesis and Evaluation of Cyclic Peptide-Based PET Tracers Targeting ADAMTS4 for Early Detection and Monitoring of...

Aortic aneurysm (AA), with high rupture risk and mortality, lacks accurate early diagnostic tools. Existing morphological imaging and [¹⁸F]FDG PET show insufficient specificity, necessitating AA-specific tracers. In this study, ADAMTS4, a regulator of vascular wall cell proliferation and collagen repair, was verified as a potential biomarker with high expression in human AA tissue. Based on an ADAMTS4-targeting peptide, PET tracer precursor series (ADA1-ADA5) with varied linkers were designed and synthesized, aiming to optimize pharmacokinetic properties. Binding assays revealed that ADA2 showed the highest ADAMTS4 binding affinity among all, with ∼4-fold improvement compared to unmodified peptide ADA0. Next, [⁶⁸Ga]ADA1-[⁶⁸Ga]ADA5 with satisfactory radiochemical properties were obtained and subjected to PET/CT imaging. [⁶⁸Ga]ADA2 exhibited optimal AA uptake and the ability to localize ∼20% dilated aorta. Furthermore, the tracer demonstrated favorable in vivo safety and reduced renal uptake, highlighting its promise for the early detection of AA progression and the identification of high-risk patients.