Delving into the Latest Updates on [18F]CHDI-650 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug, Diagnostic radiopharmaceuticals

Synonyms-

Target-

Action

enhancers

Mechanism

PET imaging(Positron-emission tomography enhancers)

Therapeutic Areas

Nervous System DiseasesCongenital DisordersOther Diseases

Active Indication

Huntington Disease

Inactive Indication-

Originator Organization

CHDI Foundation, Inc.

Active Organization

CHDI Foundation, Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: Schaertl, Sabine ; Johnson, Peter D. ; Muñoz-Sanjuan, Ignacio ; Brown, Christopher J. ; Coe, Samuel ; Veneziano, Maria ; Staelens, Steven ; Khani, Yaser ; Herrmann, Frank ; Sandiego, Christine ; Mills, Matthew R. ; Dickie, Anthony P. ; Liu, Longbin ; Chen, Xuemei ; Esposito, Simone ; Bertoglio, Daniele ; Hsai, Ming Min ; Kotey, Adrian ; Gadouleau, Elise ; Marriner, Gwendolyn A. ; Monteagudo, Edith ; Turner, Penelope A. ; Tookey, Jack ; Prime, Michael E. ; Dominguez, Celia ; Heßmann, Manuela ; Marston, Richard W. ; Vecchi, Andrea ; Orsatti, Laura ; Halldin, Christer ; Nag, Sangram ; Herbst, Todd ; Hayes, Sarah ; Bard, Jonathan ; Mangette, John E. ; Giles, Paul R. ; Sproston, Joanne ; Forsberg-Morén, Anton ; Greenaway, Catherine ; Haber, James ; Khetarpal, Vinod ; Lembo, Angelo ; Davis, Randall ; Haller, Scott ; Anzillotti, Luca

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [¹¹C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [¹⁸F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

100 Deals associated with [18F]CHDI-650

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