Synthesis, Radiochemistry, and Preclinical Assessment of the First GPR39 PET Imaging Agent

  • J Med Chem. 2026 Apr 9;69(7):7933-7944. doi: 10.1021/acs.jmedchem.5c03351.
Bhuvanachandra Bhoopal  1 ,  Krishna Kumar Gollapelli  1 ,  Naresh Damuka  1 ,  Ivan Krizan  1 ,  Mack Miller  1 ,  Ryan W Fitzgerald  1 ,  Nishka Amesar  1 ,  Dundappa Mumbaraddi  2 ,  Dongqin Zhu  3 ,  Rita Cervera-Juanes  3 ,  Pooja Jadiya  4 ,  Christopher T Whitlow  1 ,  Kiran K Solingapuram Sai  1
Affiliations
  • 1. Department of Radiology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, United States.
  • 2. Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States.
  • 3. Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, United States.
  • 4. Department of Gerontology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, United States.
PMID: 41851960 DOI: 10.1021/acs.jmedchem.5c03351
Abstract

GPR39 is a zinc-sensing G protein-coupled receptor with critical roles in neurophysiological and metabolic processes across brain, pancreas, gut, liver, and fat tissues. Activated by extracellular zinc ions, GPR39 is involved in neurodegenerative diseases including altered levels in Alzheimer's disease (AD). Quantifying GPR39 levels in vivo could significantly advance understanding of its role in various metabolic and disease processes, enabling drug development and treatment monitoring. Our study reports the synthesis, radiolabeling, and comprehensive preclinical evaluation of the first radiotracer for GPR39 imaging: [11C]TMN-OMe. The radiotracer demonstrated high radiochemical purity, molar activity, and stability in human serum. In vivo microPET/CT imaging, biodistribution, and autoradiography analyses confirmed selective binding to GPR39, with significantly reduced brain uptake in GPR39 knockout and AD mice, and in blockade conditions. Collectively, these findings support using [11C]TMN-OMe to quantify GPR39 levels in vivo and define GPR39-based imaging as a novel platform to study mechanistic changes in neurological disorders.

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