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PET ligand discovery for arginine vasopressin

Award Number: R01MH128705
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/10/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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PET ligand discovery for arginine vasopressin - Project Summary. The V1A-specific arginine vasopressin receptor has recently become the focus of CNS research when an association between the receptor gene and autism spectrum disorder (ASD) is identified. Dysregulation of V1A activity has been suggested as a fundamental mechanism underlying ASD pathophysiology. Recent studies revealed that V1A antagonists can regulate the effect of the AVP hormone, thereby tackling a potential root cause of ASD development. PET is capable of quantifying biochemical processes in vivo, and a suitable V1A PET ligand would substantially improve our understanding of V1A-mediated AVP signaling under different pathophysiological conditions, otherwise inaccessible by ex vivo (destructive) analysis, particularly in higher species. Quantification of V1A in living brain by PET would provide the assessment of distribution and expression and target engagement of new V1A- targeted neurotherapeutics. To date, no successful examples have been demonstrated to image V1A-specific AVP for human use, representing a significant deficiency of our ability to study this target in vivo for V1A. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool. The PI has recently developed a novel V1A-specific AVP ligand [11C]PF-184563 at MGH in 2021. While this compound showed high potency and excellent selectivity, it is not likely pursued due to low brain penetration. In our 2nd generation, we identified a lead molecule, V1A-214, which showed substantially-improved binding affinity and excellent target selectivity among all other major CNS targets. An 11C-isotopologue of V1A-214 was synthesized and preliminary PET imaging studies confirmed that we have overcome two major obstacles for V1A-specific PET ligand development by achieving: 1) high brain uptake (>1 SUV) and 2) high target specificity validated by human V1A cell lines and blocking studies in vivo, and heterogenous uptake consistent with V1A regions in the CNS. Though V1A- 214 is a promising lead molecule for the development of new V1A-targeted PET ligands, due to species difference, further optimization for translational cross-species (naïve/humanized V1A mice and nonhuman primates) imaging studies are sought to achieve optimal AVP (V1A subunit) quantification in the living brain for drug discovery and clinical biomarker for ASD patients. On the basis that V1A-214 serves a validated lead for medicinal chemistry optimization, as specific objectives, we will design and prepare a focused library of V1A-specific antagonists amenable for labeling with 11C or 18F, and evaluate their ability to quantify V1A-specific AVP activity and changes in cellular experiments, naïve and humanized V1A mice and nonhuman primates, as well as autoradiography and biological validation in postmortem NHP/human brain tissues. The impact of this work is not only to develop the first successful high-affinity and selective V1A-specific PET ligand for the study of ASD-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand as a potential clinical biomarker and for monitoring target response of novel therapeutics for neurodevelopmental diseases and neuropsychiatric disorders, including ASD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,159,299 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	5	4/17/2026	NON-COMPETING CONTINUATION	$1,159,299
														Subtotal = $1,159,299

Issue Date FY: 2025 ( Subtotal = $1,178,805 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	4	6/17/2025	NON-COMPETING CONTINUATION	$1,178,805
														Subtotal = $1,178,805

Issue Date FY: 2024 ( Subtotal = $1,188,059 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	3	4/26/2024	NON-COMPETING CONTINUATION	$1,188,059
														Subtotal = $1,188,059

Issue Date FY: 2023 ( Subtotal = $1,214,143 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	2	5/5/2023	NON-COMPETING CONTINUATION	$1,214,143
														Subtotal = $1,214,143

Issue Date FY: 2022 ( Subtotal = $1,043,141 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Mental Health Research Grants	000	1	6/9/2022	NEW	$1,043,141
														Subtotal = $1,043,141

Grand Total All Awards = $5,783,447

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PET ligand discovery for arginine vasopressin

Award Number: R01MH128705

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/10/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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