PET Imaging of brain muscarinic receptors with 18F-Fluorobenzyl-Dexetimide: A first in human study

Christopher C Rowe; Natasha Krishnadas; Uwe Ackermann; Vincent Doré; Rachel Y W Goh; Rodney Guzman; Lee Chong; Svetlana Bozinovski; Rachel Mulligan; Richard Kanaan; Brian Dean; Victor L Villemagne

doi:10.1016/j.pscychresns.2021.111354

PET Imaging of brain muscarinic receptors with ¹⁸F-Fluorobenzyl-Dexetimide: A first in human study

Psychiatry Res Neuroimaging. 2021 Oct 30:316:111354. doi: 10.1016/j.pscychresns.2021.111354. Epub 2021 Aug 8.

Affiliations

¹ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia; The Florey Department of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, 3070, Australia. Electronic address: christopher.rowe@austin.org.au.
² Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia.
³ Department of Molecular Imaging & Therapy, Austin Health, Heidelberg, Victoria, 3084, Australia; The Australian e-Health Research Centre, CSIRO Health & Biosecurity, Parkville, Victoria, 3052, Australia.
⁴ Department of Psychiatry, University of Melbourne, Austin Health, Heidelberg, Victoria, 3070, Australia.
⁵ The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3052, Australia; The Centre for Mental Health, Swinburne University, Hawthorn, Victoria, 3122, Australia.

PMID: 34399286
DOI: 10.1016/j.pscychresns.2021.111354

Abstract

M1 and M4 muscarinic receptor (mAChR) agonists are under development for the treatment of schizophrenia, Alzheimer's and Parkinson's disease. We performed first-in-human PET imaging of mAChR with ¹⁸F-Fluorobenzyl-Dexetimide (FDEX) in 10 healthy participants (29.4±4.3yrs). Four underwent dynamic brain scanning for 240 min, and then six underwent static brain scans at 120 and 160-min post injection of 250 MBq of FDEX. Gjedde-Patlak graphical analysis was applied to determine the influx constant (Ki). Regional tissue ratios (SUVR) were calculated using the cerebellar cortex as the reference region. No adverse events were observed. The tracer showed good brain entry (∼4.2% ID at 5 min) but irreversible distribution kinetics over four hours in regions of high mAChR. Binding was consistent with the distribution of mAChR receptors with striatum > cortex > hippocampus >> thalamus >>> cerebellum with low variance in regional binding between subjects. Ki was 0.42±0.04 in the putamen, 0.27±0.01 in frontal cortex, 0.25±0.02 in the hippocampus and 0.10±0.01 in the thalamus. SUVR at 120 and 240 min. were highly correlated with these Ki values with R² of 0.91 and 0.99 respectively. FDEX yields high quality brain images with uptake in the known distribution of mAChR with remarkably little variance between normal subjects.

Keywords: Brain distribution; Fluorine-18; Muscarinic acetylcholine receptors; Neuroreceptor imaging; Positron emission tomography; Radiopharmaceutical; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Brain / diagnostic imaging
Brain / metabolism
Dexetimide*
Humans
Kinetics
Positron-Emission Tomography*
Receptors, Muscarinic / metabolism

Substances

Receptors, Muscarinic
Dexetimide