RT Journal Article SR Electronic T1 [11C]Deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 120 OP 120 VO 62 IS supplement 1 A1 Yan, Xuefeng A1 Telu, Sanjay A1 Dick, Rachel A1 Liow, Jeih-San A1 Zanotti-Fregonara, Paolo A1 Morse, Cheryl A1 Manly, Lester A1 Gladding, Robert A1 Shrestha, Stal A1 Lerchner, Walter A1 Nagai, Yuji A1 Minamimoto, Takafumi A1 Zoghbi, Sami A1 Innis, Robert A1 Pike, Victor A1 Richmond, Barry A1 Eldridge, Mark YR 2021 UL http://jnm.snmjournals.org/content/62/supplement_1/120.abstract AB 120Introduction: A previous study found that [11C]deschloroclozapine ([11C]DCZ) is a superior radiotracer to [11C]clozapine ([11C]CLZ) for imaging DREADDS1. Building on this work, the present study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions in order to assess the qualities that contribute to this superiority. Methods: A genetically modified muscarinic type 4 human receptor (hM4Di) was injected into the right amygdala of an 11-year-old male rhesus macaque. PET scans with [11C]DCZ and [11C]CLZ were conducted two to 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). For [11C]CLZ, the three blocking studies and i.v. doses were: a) clozapine-N-oxide (CNO) (10 mg/kg), b) CLZ (0.1 mg/kg), and c) clotrimazole (CTM; 1 mg/kg) plus CNO (10 mg/kg). For [11C]DCZ, the three blocking studies and i.v. doses were: a) CNO (10mg/kg), b) low-dose DCZ (0.1 mg/kg), and c) high-dose DCZ (1 mg/kg). To assess the radiotracers’ transfer between plasma and brain quantitatively, eight different VOI-based methods were performed: the one- and two-tissue compartment models, Ichise’s multilinear reference tissue models (MRTM, MRTM0, and MRTM2), simplified reference models (SRTM and SRTM2), and Logan’s reference tissue model (Logan-REF). The cerebellum was used as the reference region.Results: Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed and might represent off-target binding to endogenous receptor(s). After correction, the [11C]DCZ signal was 19% of that for [11C]CLZ, and the background uptake of [11C]DCZ was 10% of that for [11C]CLZ. Despite stronger binding of [11C]CLZ, 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.Conclusion: Both [11C]DCZ and [11C]DCZ had high-affinity displaceable binding to DREADDs relative to endogenous receptor(s), However, the signal-to-background ratio of [11C]DCZ was greater than that of [11C]CLZ primarily because of lower nonspecific binding of [11C]DCZ. Reference tissue models underestimated the signal-to-background ratio compared to two tissue compartmental model. Nevertheless, the use of a pseudo-reference region should provide useful information on the localization and comparative quantitation of the transfected receptor. Our results confirm that [11C]DCZ is far superior to [11C]CLZ to image the hM4Di DREADD for behavioral and translational experiments.References: 1. Nagai Y, Miyakawa N, Takuwa H, et al. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nature Neuroscience volume 23, pages1157-1167(2020)