# A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia

> **NIH NIH U01** · YALE UNIVERSITY · 2022 · $3,675,188

## Abstract

PROJECT SUMMARY
This UO1 application is a response to the NIMH Program Announcement intended to accelerate the development of a high
priority therapeutic agent by establishing its dose-related pharmacodynamic effects on biomarkers designed to inform subse-
quent clinical development. Dopamine D1 receptor (D1R) agonism is among the most highly prioritized adjunctive treatment
mechanisms for schizophrenia. Currently, all D1R agonists are also D5R agonists. D1R/D5R agonists have pro-cognitive
and antipsychotic-like effects in preclinical studies, reflecting their ability to stabilize prefrontal cortical network activity in
the face of distractors, and to enhance the precision of spatial working memory (sWM) by enhancing inhibitory tuning of
prefrontal cortical (PFC) functional connectivity (FC). Yet, dose-related benefits of D1R/D5R agonism in patients could not
be demonstrated in prior pilot studies. This application proposes that the testing of D1R/D5R agonists requires both a more
direct translational/computational neuroscience framework (i.e., the most appropriate biomarkers) and a precision medicine
strategy (i.e., the appropriate subpopulation of patients). To accelerate the selection of an optimal dose, we propose a multi-
center study that densely maps the dose-related effects of the D1R/D5R partial agonist, PF-06412562 immediate release (IR),
on three informative translational functional neuroimaging (fMRI) biomarkers as primary outcome measures: i) sWM-related
activation; ii) task-based FC; and iii) resting-state FC in early course schizophrenia patients. Primary Aim 1 will apply a mul-
tivariate analytic strategy to these three outcome measures (sWM-related activation, task-based FC and resting-state FC) to
test if PF-06412562 produces a dose-related effect. This multivariate translational neural marker is designed and powered to
inform a clear Go/No-Go decision with regards to proceeding to a full-scale clinical trial. A Go decision will be indicated if
there is a significant dose-related drug effect on the neural signal measured via the multivariate combination of task-evoked
activation and FC during the sWM task and FC during rest. Conversely, a No-Go decision will be reached if there is an
absence of a dose-related effect on the multivariate index. Secondary Aim 2 will quantify dose-related drug effects on sWM
precision based on behavioral data collected during fMRI. Exploratory Aim 3 will model the biophysical properties of PF-
06412562 in a cortical circuit model capable of sWM simulations, which will simulate hypothesized molecular mechanisms
governing pro-cognitive PF-06412562 effects on sWM. In turn, we will will test if the dose-related pattern of PF-06412562
effects on resting FC in patients maps onto D1R and D5R receptor transcriptomic profiles in humans derived from from Allen
Human Brain Atlas. Finally, Exploratory Aim 4 will study potential clinical predictors and moderators of PF-06412562 ef-
fects on neuroimaging biomarke...

## Key facts

- **NIH application ID:** 10248465
- **Project number:** 5U01MH121766-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** John H. Krystal
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $3,675,188
- **Award type:** 5
- **Project period:** 2019-09-23 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248465

## Citation

> US National Institutes of Health, RePORTER application 10248465, A Translational and Neurocomputational Evaluation of a D1R Partial Agonist for Schizophrenia (5U01MH121766-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248465. Licensed CC0.

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