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Lookup NU author(s): Dr Mark EldridgeORCiD
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© The Author(s) 2021. Previous work found that [11C]deschloroclozapine ([11C]DCZ) is superior to [11C]clozapine ([11C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4Di) was injected into the right amygdala of a male rhesus macaque. [11C]DCZ and [11C]CLZ PET scans were conducted 2–24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [11C]DCZ signal was 19% of that for [11C]CLZ, and background uptake was 10% of that for [11C]CLZ. Despite stronger [11C]CLZ binding, the signal-to-background ratio for [11C]DCZ was almost two-fold greater than for [11C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%–50% for both radioligands. Thus, the greater signal-to-background ratio of [11C]DCZ was due to its lower background uptake.
Author(s): Yan X, Telu S, Dick RM, Liow J-S, Zanotti-Fregonara P, Morse CL, Manly LS, Gladding RL, Shrestha S, Lerchner W, Nagai Y, Minamimoto T, Zoghbi SS, Innis RB, Pike VW, Richmond BJ, Eldridge MAG
Publication type: Article
Publication status: Published
Journal: Journal of Cerebral Blood Flow and Metabolism
Year: 2021
Volume: 41
Issue: 10
Pages: 2571-2582
Print publication date: 01/10/2021
Online publication date: 14/04/2021
Acceptance date: 08/03/2021
ISSN (print): 0271-678X
ISSN (electronic): 1559-7016
Publisher: SAGE Publications Ltd
URL: https://doi.org/10.1177/0271678X211007949
DOI: 10.1177/0271678X211007949
PubMed id: 33853405
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