A Program for Innovative PET Radioligand Development and Application - A Translational Toolbox for Treatments for Mental Health

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Project Summary/Abstract Advances in molecular neuroscience, genetics, and basic behavioral science have vastly expanded our knowledge and understanding on the etiology and pathophysiology of mental illness, and identified new molecular targets for therapeutic development. PET imaging has similarly expanded dramatically and now provides critical translational tools for molecular imaging and therapeutic development in mental disorders. PET imaging with target-specific radioligands has played a critical role in the elucidation of molecular targets, such as receptors and transporters for the dopamine, serotonin, opioid, GABA, glutamate, endocannabinoid, and acetylcholine systems, in the pathophysiology of depression, schizophrenia, and other mental disorders. The availability of suitable radioligands is key to exploring the full potential of PET imaging in mental health research. The goal of this renewal application is to advance an innovative program in the development, validation, and application of novel PET radioligands to probe high priority molecular targets implicated in mental health disorders. This program builds on the Yale PET Center's outstanding capability in radioligand development and clinical evaluation. We use a tiered development strategy: Tier 1 - Chemistry development and in vitro testing; Tier 2 - In vivo assessment in non-human primates; Tier 3 – First-in-human proof of concept/validation studies; and Tier 4 - Application to investigate mechanisms of mental illnesses. Radioligands enter the development scheme at any tier when there is sufficient rationale that advancing the radioligand can inform disease mechanisms of relevant mental disorders. The program's External Scientific Panel and Steering Committee (NIMH program leaders, industry and academic subject-matter experts, and Yale scientists) hold annual meetings to nominate new targets and review ongoing data to optimize the radioligand pipeline. Radioligands developed and data generated under the program are disseminated via a dedicated website, conference presentations and publications, and shared with the PET imaging and mental health research community. This program aligns tightly with NIMH priorities by involvement of NIMH program officers in the decision- making process, and engages the entire PET tracer development and imaging community in the common endeavor to validate novel radioligands for molecular targets important in mental health research. The initial funding cycle resulted in the validation of a novel agonist tracer for the dopamine D1 receptor, the first-in-human testing of radiotracers for histone deacetylase 6 (HDAC6) and monoacylglycerol lipase (MAGL), and most significantly, the development of first-in-class radiotracers for the GABA transporter-1 (GAT-1), and best-in-class radiotracer for the GluN2B subunit of the NMDA receptor complex, which we propose to translate to first-in- human evaluation in this renewal application. Success in the next cycle will see validation of first-in-class and best-in-class radiotracers for imaging and quantification of GAT-1, GluN2B, and AMPA receptors in humans, and development of novel radiotracers for new targets to advance mental health research through PET imaging.