# Dopamine-induced PET occupancy explored by PET/fMRI

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $656,549

## Abstract

Abstract
Non-invasive neuroimaging has become a dominant tool in studies of human brain function in
health and disease. Currently, PET represents our only tool for non-invasively probing
neurotransmitter release, with the majority of such studies focusing on the dopamine system.
Despite the exquisite molecular specificity to some of the neurochemical processes underlying brain
activation, questions remain about the source of the PET signal and the accuracy of inferences
based upon displacement of radiotracer. In order to address these issues, we propose
mechanistic studies and better characterization of an agonist radiotracer ([11C]PHNO) that
promises better sensitivity to dopamine release. To help interpret the source of signal, our recent
work has focused upon combining PET with concurrent fMRI in order to supplement the
neurochemical signature provided by PET measurements of receptor occupancy with an fMRI
readout describing the functional consequences of that occupancy. In order to set the stage for
extracting subtle changes in PET occupancy, we have described a refined PET tracer-kinetic
model that should reduce systematic bias. In order to understand the relationship of fMRI signals
to changes in occupancy, we have developed simple single and multi-receptor models of
dopamine-induced fMRI signal. In accordance with prior PET work that indirectly suggested
divergent responses to receptor agonists and antagonists that might be indicative of neuroreceptor
trafficking, we have identified different PET/fMRI relationships for agonists versus antagonists. In
the proposed studies, we will utilize a mouse knock-out model in conjunction with dopamine
microdialysis to more directly test hypotheses about how receptor trafficking influences PET and
fMRI signals, and we will perform studies in non-human primates (NHP) on clinical scanners to
demonstrate effects of acute and chronic dopamine stimulation using two different radiotracers
([11C]PHNO and [11C]raclopride). We will utilize unilateral deep brain stimulation (DBS) in NHP to
produce a unilateral, focal, and titratable model of dopamine release that can be validated by
simultaneous fMRI and used to compare the sensitivity of each radiotracer to dopamine
release. As a translational complement, we will perform studies in healthy human volunteers to
test the magnitude of behaviorally-modulated dopamine using 11C]PHNO and [11C]raclopride and
characterize the spatial response versus simultaneously acquired fMRI. The proposed studies will
help improve our understanding of PET measurements of endogenous neurotransmitter release
and may lead to more robust measurements of behaviorally modulated dopamine release in
human subjects.

## Key facts

- **NIH application ID:** 9926322
- **Project number:** 5R01NS112295-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JOSEPH B MANDEVILLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $656,549
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926322

## Citation

> US National Institutes of Health, RePORTER application 9926322, Dopamine-induced PET occupancy explored by PET/fMRI (5R01NS112295-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9926322. Licensed CC0.

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