# A new P2Y12R PET radioligand for measuring microglial function in Alzheimer's disease

> **NIH NIH R21** · STANFORD UNIVERSITY · 2022 · $436,144

## Abstract

SUMMARY
Alzheimer's disease (AD) is the most common form of dementia in older adults and the 6th leading cause of
death in the United States. Unfortunately, there are currently no FDA approved disease-modifying therapeutics
available for AD, and definitive diagnosis is only possible via postmortem analysis. The limited number of
sensitive biomarkers enabling detection of early, functionally relevant, neuromolecular changes in AD is a major
impediment to improving diagnosis and validating novel therapeutics. Although data from genome wide
association studies and immunohistochemistry have implicated neuroinflammation and a loss of healthy innate
immune function as major AD risk factors, biomarkers to investigate neuro-immune function preceding and
during AD remain extremely limited. Positron Emission Tomography (PET) is an highly sensitive molecular
imaging modality well suited to studying such biomarkers longitudinally, with established utility for non-invasive
in vivo interrogation of biochemical processes. Existing PET imaging biomarkers of neuroinflammation (e.g., the
translocator protein 18 kDa [TSPO]) suffer from significant drawbacks, including a poorly elucidated functional
role and/or expression across multiple cell types in the central nervous system (CNS), which complicates image
analysis. Within the CNS, adenosine diphosphate receptor (P2Y12R) expression is restricted to microglia, the
innate immune effector cells of the brain. Generally considered a biomarker of homeostatic microglia, P2Y12R
expression drives chemotaxis and activation-associated morphological changes. Importantly, P2Y12R
expression decreases in both acute and chronic neuroinflammation, as shown in rodents after lipopolysaccharide
challenge and in AD transgenic mice. Moreover, postmortem human brain tissue from advanced AD patients
demonstrated global reduction in P2Y12R expression, with a near total absence on microglia surrounding
amyloid-beta plaques. While P2Y12R is an extremely well characterized pharmacological target, there are
currently no CNS-penetrable PET radiotracers for this biomarker. We have identified the P2Y12R antagonist
AZD1283 as a promising potential PET tracer based on its high affinity and favorable lipophilicity (measured
LogD 2.8) indicative of its high likelihood for CNS uptake. Upon optimization of the cyanation radiochemistry
outlined herein, we propose to assess the in vivo kinetics, biodistribution, stability, and specificity of
[11C]AZD1283 in healthy mice, as well as the ability of [11C]AZD1283 to detect alterations in P2Y12R expression
in human AD postmortem tissue using autoradiography (Aim 1). Additionally, we will interrogate the dynamics of
microglial P2Y12R expression in two murine models of acute and chronic neuroinflammation (Aim 2). Completion
of these aims will result in development and characterization of the first P2Y12R PET tracer suitable for in vivo
PET imaging, with high potential for clinical translation. Ultimately, such...

## Key facts

- **NIH application ID:** 10355306
- **Project number:** 1R21AG075565-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michelle Louise James
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $436,144
- **Award type:** 1
- **Project period:** 2022-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355306

## Citation

> US National Institutes of Health, RePORTER application 10355306, A new P2Y12R PET radioligand for measuring microglial function in Alzheimer's disease (1R21AG075565-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10355306. Licensed CC0.

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