In vitro evaluation of PET radiotracers for imaging synaptic density, the acetylcholine transporter, AMPA-tarp-γ8 and muscarinic M4 receptors in Alzheimer's disease

Faustine d'Orchymont; Andrea Narvaez; Roger Raymond; Pallavi Sachdev; Arnaud Charil; Stephen Krause; Neil Vasdev

doi:10.62347/USWK7545

In vitro evaluation of PET radiotracers for imaging synaptic density, the acetylcholine transporter, AMPA-tarp-γ8 and muscarinic M4 receptors in Alzheimer's disease

Am J Nucl Med Mol Imaging. 2024 Feb 20;14(1):1-12. doi: 10.62347/USWK7545. eCollection 2024.

Authors

Faustine d'Orchymont¹, Andrea Narvaez^{1

2}, Roger Raymond¹, Pallavi Sachdev³, Arnaud Charil³, Stephen Krause³, Neil Vasdev^{1

4}

Affiliations

¹ Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health (CAMH) Toronto, ON, Canada.
² Enigma Biomedical Group, Inc. Toronto, ON, Canada.
³ Eisai, Inc. Nutley, NJ, USA.
⁴ Department of Psychiatry, University of Toronto Toronto, ON, Canada.

Abstract

Several therapeutics and biomarkers that target Alzheimer's disease (AD) are under development. Our clinical positron emission tomography (PET) research programs are interested in six radiopharmaceuticals to image patients with AD and related dementias, specifically [¹¹C]UCB-J and [¹⁸F]SynVesT-1 for synaptic vesicle glycoprotein 2A as a marker of synaptic density, two vesicular acetylcholine transporter PET radiotracers: [¹⁸F]FEOBV and [¹⁸F]VAT, as well as the transmembrane AMPA receptor regulatory protein (TARP)-γ8 tracer, [¹⁸F]JNJ-64511070, and the muscarinic acetylcholine receptor (mAChR) M4 tracer [¹¹C]MK-6884. The goal of this study was to compare all six radiotracers (labeled with tritium or ¹⁸F) by measuring their density variability in pathologically diagnosed cases of AD, mild cognitive impairment (MCI) and normal healthy volunteer (NHV) human brains, using thin-section in vitro autoradiography (ARG). Region of interest analysis was used to quantify radioligand binding density and determine whether the radioligands provide a signal-to-noise ratio optimal for showing changes in binding. Our preliminary study confirmed that all six radiotracers show specific binding in MCI and AD. An expected decrease in their respective target density in human AD hippocampus tissues compared to NHV was observed with [³H]UCB-J, [³H]SynVesT-1, [³H]JNJ-64511070, and [³H]MK-6884. This preliminary study will be used to guide human PET imaging of SV2A, TARP-γ8 and the mAChR M4 subtype for imaging in AD and related dementias.

Keywords: Alzheimer’s disease; Autoradiography; PET; SV2A; SynVesT-1; cholinergic; fluorine-18; glutamatergic; synaptic density; tritium.