PDE4D PET Ligand for Psychiatric Disease

Tetra Discovery Partners is the recipient of an NIH Blueprint Neurotherapeutics Network award to develop phosphodiesterase D PDE D Negative Allosteric Modulators NAMs for treating memory loss in patients affected by psychiatric and neurologic diseases The Tetra NIH Blueprint drug is projected to reach human Phase I clinical trials in late Through a Cooperative Research and Development Agreement CRADA with Dr Robert Innis and Dr Victor Pike of the NIMH Intramural Program the company has been working in parallel to develop novel PET ligands for imaging PDE subtypes in the human brain The goal of the proposed Phase I SBIR is to develop a PDE D PET ligand useful for assessing target occupancy in human Phase I clinical trials of the Tetra NIH Blueprint drug as well as a PET ligand that will be useful for assessing PDE D levels in patients with psychiatric and neurologic disease PDE D as a target for improving cognition in humans has genetic validation through studies of children with PDE D gene mutations who develop an ultra rare disorder known as acrodysostosis type ACRDY MIM ACRDY is a developmental disorder characterized by intellectual disability brachydactyly nasal hypoplasia and short stature Children with acrodysostosis only achieve an IQ of Thus PDE D is the human ortholog of the Drosophila PDE gene in which the Dunce mutation was the first learning mutation identified in a model organism Rolipram and other PDE inhibitors have been shown to be broadly pro cognitive in numerous animal models of learning and memory while knock out or knock down of the mouse PDE D gene also improves learning and memory Our NIMH collaborators Innis and Pike have shown that PDE PET imaging is altered in patients with major depression Those studies used C R rolipram as a PET ligand for assessing PDE levels however rolipram binds equally to the different subtypes of PDE expressed in brain PDE A PDE B andamp PDE D We therefore want to understand if PDE D levels are altered in major depression and other psychiatric diseases In the Phase I SBIR Tetra will optimize potent and selective PDE D NAMs for C or F labelling by Innis and Pike who will conduct in vivo PET imaging studies Should a suitable PDE D PET ligand be identified the imaging agent could rapidly advance into human clinical trials PUBLIC HEALTH RELEVANCE The company has developed a mechanistically novel class of drugs to address cognitive impairment across multiple psychiatric and neurological indications These new drugs are Negative Allosteric Modulators NAMs of phosphodiesterase D PDE D The SBIR project will develop a PDE D selective PET ligand to be used in human Phase I clinical trials of the cognition drug to assess PDE D target occupancy