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

  • J Med Chem. 2025 Dec 11;68(23):25403-25415. doi: 10.1021/acs.jmedchem.5c02380.
Hongyi Huang  1 ,  Quan Zuo  1 ,  Siqi Zhang  1 ,  Zirui Zhang  1 ,  Xiaona Sun  1 ,  Jiang Wu  2 ,  Jie Yan  1 ,  Maoqing Jiang  3 ,  Minzi Lu  1 ,  Feng Wang  2 ,  Rui Wang  1 ,  Xiaohui Ma  4 ,  Kuan Hu  1
Affiliations
  • 1. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2. Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 3. Department of Radiology, Ningbo No. 2 Hospital, Ningbo 315000, China.
  • 4. Department of Vascular Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
PMID: 41324323 DOI: 10.1021/acs.jmedchem.5c02380
Abstract

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.

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