[ 11 C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain.

Autor: Yan X; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Telu S; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Dick RM; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Liow JS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Zanotti-Fregonara P; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Morse CL; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Manly LS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Gladding RL; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Shrestha S; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Lerchner W; Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Nagai Y; Department of Functional Brain Imaging, National institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan., Minamimoto T; Department of Functional Brain Imaging, National institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan., Zoghbi SS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Innis RB; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Pike VW; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Richmond BJ; Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA., Eldridge MA; Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2021 Oct; Vol. 41 (10), pp. 2571-2582. Date of Electronic Publication: 2021 Apr 14.
DOI: 10.1177/0271678X211007949
Abstrakt: Previous work found that [ 11 C]deschloroclozapine ([ 11 C]DCZ) is superior to [ 11 C]clozapine ([ 11 C]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 (hM 4 Di) was injected into the right amygdala of a male rhesus macaque. [ 11 C]DCZ and [ 11 C]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, [ 11 C]DCZ signal was 19% of that for [ 11 C]CLZ, and background uptake was 10% of that for [ 11 C]CLZ. Despite stronger [ 11 C]CLZ binding, the signal-to-background ratio for [ 11 C]DCZ was almost two-fold greater than for [ 11 C]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 [ 11 C]DCZ was due to its lower background uptake.
Databáze: MEDLINE
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