# Neuroimaging of PDE10A

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $615,283

## Abstract

ABSTRACT
Multiple neurologic and psychiatric disorders including Parkinson disease (PD), Huntingon disease (HD),
dystonia and schizophrenia involve dopaminergic (DA) pathways as part of pathophysiology or treatment.
Changes in function of nigrostriatal pathways may reflect either presynaptic or postsynaptic effects. Most
previous studies focused on presynaptic changes. This proposal focuses on phosphodiesterases (PDEs) that
control signal transduction of both families of DA receptors (D1-like and D2-like). PDE10A, the PDE subtype
restricted to striatal medium spiny neurons (MSNs) and is expressed in direct (mosty D1-mediated) and indirect
pathway neurons (mostly D2-mediated). PET ligands for PDE10A could facilitate study of pathophysiology,
disease progression or target engagement for diseases with striatal pathologies such as PD or HD. However,
the interactions among presynaptic nigrostriatal neurons, DA receptors, behavior and PDE10A remain
unknown. Failure to understand these relationships led to confusion about interpretation of clinical studies
using presynaptic molecular DA biomarkers. Molecular imaging measures also may be altered by either acute
or chronic drug exposures, thus investigation of those potential effects also will permit unabmiguous
interpretation of human studies. This proposal will help prevent such confusion by directly determining the
effects of nigrostriatal injury on striatal PDE10A, comparing with presynaptic measures, D1-like and D2-like DA
receptors, other striatal neurotransmitters and motor behavior in nonhuman primates (NHPs).
We will leverage previously collected tissues from NHPs that have been treated with varying doses of
intracarotid (ic) MPTP that causes graded degrees of nigrostriatal injury. We also will study new NHPs to
determine the relationships between in vivo PET measures of PDE10A with other presynaptic and postsynaptic
biomarkers. We will use two different PET radioligands for PDE10A that have different tracer kinetic properties.
Finally, we will determine the effects of acute or chronic drugs on in vivo PDE10A in striatum since drug effects
can be a major confound in human imaging studies, particularly of dopaminergic pathways. These proposed
studies will permit unambiguous interpretation of PDE10A PET radioligands to investigate relevant
pathophysiologies or provide measures of target engagement of new therapies for PD, HD and possibly
psychosis.

## Key facts

- **NIH application ID:** 10240319
- **Project number:** 5R01NS103957-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JOEL Synes PERLMUTTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $615,283
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240319

## Citation

> US National Institutes of Health, RePORTER application 10240319, Neuroimaging of PDE10A (5R01NS103957-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240319. Licensed CC0.

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