Work

Development of a Novel PET Radioligand Targeting PKM2 for Brain Imaging and Alzheimer’s Disease Characterization

Year: 2025

Type: article

Abstract: Targeting pyruvate kinase M2 (PKM2) offers a route to probe neuroinflammatory metabolism in Alzheimer’s disease (AD). We report the radiosynthesis and preclinical evaluation of a PKM2-targeted PET radioligand, [11C]7d. [11C]7d was produced in 21.6–29.4% decay-corrected yield from trapped [11C]CH3I with >95% radiochemical purity. Whole-body PET (0–60 min) indicated predominantly hepatobiliary clearance with modest renal excretion. In wild-type mice, [11C]7d showed rapid brain entry followed by washout consistent with reversible kinetics. Pharmacological pretreatment with 7d reduced whole-brain AUC, indicating displaceable binding. Ex vivo autoradiography showed a 62.8% signal reduction with 7d and ∼20.1% higher binding in 5xFAD versus NonTg sections. In vivo, 5xFAD mice displayed higher uptake; cerebellum normalized SUVR(20–60 min) increased across multiple regions. PKM2 immunohistochemistry supported regional target engagement. These data support [11C]7d as a tool for noninvasive visualization of PKM2-linked glycolytic alterations in the living brain and motivate further quantitative and translational studies.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c02549