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

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.