[ <sup>11</sup> C]deschloroclozapine is an improved PET radioligand for quantifying a human muscarinic DREADD expressed in monkey brain
Xuefeng Yan, Sanjay Telu, Rachel M. Dick, Jeih‐San Liow, Paolo Zanotti‐Fregonara, Cheryl L. Morse, Lester S. Manly, Robert L. Gladding, Saurav Shrestha, Walter Lerchner, Yuji Nagai, Takafumi Minamimoto, Sami S. Zoghbi, Robert B. Innis, Victor W. Pike, Barry J. Richmond, Mark A. G. Eldridge
Abstract
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.