Kinetically Inert MRI/PET Probes with Myeloperoxidase-Triggered Covalent Capture for Quantitative Imaging of Acute Pancreatitis

  • J Med Chem. 2026 Jun 11;69(11):13670-13682. doi: 10.1021/acs.jmedchem.6c00609.
Tiantian Luo  1  2 ,  Lu Liu  3 ,  Jie Yang  1 ,  Xinyi Gao  1  4 ,  Wanyin Yang  1  4 ,  Zhengwei Li  1  4 ,  Xiaoya Liu  1 ,  Lei Zhong  1 ,  Xinghui Li  1 ,  Zhiyang Xia  4 ,  Zuhua Zeng  5 ,  Jiang Zhu  1  6
Affiliations
  • 1. Medical Imaging Key Laboratory of Sichuan Province, School of Medical Imaging, North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  • 2. School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  • 3. Department of Radiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
  • 4. School of Basic Medical Sciences and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  • 5. Department of Gynecology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  • 6. Department of Nuclear Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, China.
PMID: 42154911 DOI: 10.1021/acs.jmedchem.6c00609
Abstract

Myeloperoxidase (MPO)-mediated oxidative stress drives inflammatory tissue injury, yet converting this enzyme activity into a selective and sustained imaging readout remains chemically challenging. To address this limitation, we report Mn-TyrCDTA, a manganese chelate designed to couple kinetic inertness with MPO-triggered activation and retention mechanism. Replacement of a flexible EDTA backbone with a rigidified CDTA scaffold improved the kinetic inertness 3-fold under a Zn2+ challenge (dissociation t1/2 = 61.7 min). Incorporation of a tyramine-derived phenolic moiety enabled MPO/H2O2-mediated, one-electron oxidation and covalent protein anchoring, resulting in a 3.6-fold relaxivity enhancement and prolonged inflamed tissue retention. In rat models of acute pancreatitis, contrast enhancement correlated with tissue MPO activity (R2 = 0.83), enabling quantitative disease severity stratification. Complementary 68Ga-TyrCDTA PET studies demonstrated enzyme-dependent tracer accumulation, and MPO inhibition reduced the imaging signal by 85% (R2 = 0.98). These findings establish a rational design framework for the quantitative imaging of neutrophil-driven oxidative tissue injury.

Products