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Development of a Novel PET Radioligand Targeting PKM2 for Brain Imaging and Alzheimer's Disease Characterization
Yanli Wang1, Yongle Wang1, Wei Zhang2
1Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
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.
Insights
Researchers developed a novel PET radioligand, [11C]7d, to visualize pyruvate kinase M2 (PKM2) in Alzheimer's disease (AD) models. This tool helps study neuroinflammation and metabolic changes in the brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Radiochemistry
Background:
- Alzheimer's disease (AD) involves neuroinflammation and altered cellular metabolism.
- Pyruvate kinase M2 (PKM2) is implicated in the metabolic reprogramming observed in AD.
- Noninvasive imaging tools are needed to study PKM2-related metabolic changes in vivo.
Purpose of the Study:
- To develop and evaluate a novel positron emission tomography (PET) radioligand targeting PKM2.
- To assess the utility of the radioligand, [11C]7d, for visualizing PKM2 in preclinical models of Alzheimer's disease.
Main Methods:
- Radiosynthesis of the carbon-11 labeled PET tracer [11C]7d.
- Preclinical evaluation in wild-type and 5xFAD mouse models of Alzheimer's disease.
- Whole-body PET imaging, ex vivo autoradiography, and immunohistochemistry to assess target engagement and biodistribution.
Main Results:
- [11C]7d was successfully synthesized with high radiochemical purity and yield.
- The radioligand demonstrated rapid brain entry and reversible kinetics in wild-type mice.
- 5xFAD mice showed increased [11C]7d uptake in brain regions compared to non-transgenic controls, consistent with PKM2 upregulation.
Conclusions:
- [11C]7d serves as a valuable tool for noninvasive imaging of PKM2-associated glycolytic alterations in the brain.
- The findings support the potential of [11C]7d for studying neuroinflammation and metabolic dysregulation in Alzheimer's disease.
- Further quantitative and translational studies are warranted to validate its clinical utility.
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