Abstract
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Objectives 11C-CUMI-101 is an agonist radioligand for the serotonin subtype 1A (5-HT1A) receptor. Since some 5-HT1A receptor agonists also have significant affinity for alpha-1 adrenoceptors, we evaluated 11C-CUMI-101 in rodents and monkeys for potential binding to this alpha-1adrenoceptor.
Methods Dynamic PET scans were acquired in male rats and male rhesus monkeys at baseline and after blockade of: 1) only 5-HT1A receptors using WAY 100635 (WAY); 0.5 mg/kg; 2) only alpha-1 adrenoceptors using prazosin; 2.0 mg/kg; and 3) both 5-HT1A and alpha-1 adrenoceptors using WAY plus prazosin. We performed 3 PET scans in rats and 4 in monkeys. Binding potential (BPND) was calculated using the cerebellum as the reference tissue.
Results In rats, WAY incompletely blocked brain uptake of radioactivity in a region-dependent manner (BPND reduced by 25-75%). Prazosin significantly blocked (BPND reduced >70%) uptake in thalamus, which has a high density of alpha-1 receptors. WAY plus prazosin blocked uptake in all regions down to the level in cerebellum (BPND reduced > 80%). In monkeys, WAY reduced BPND by > 80% in all brain regions except thalamus (47%). Prazosin decreased BPND in monkey thalamus by 30% but had negligible effects in other regions with moderate to high densities of 5-HT1A receptors, including all neocortex, hippocampus, and amygdala. In these 5-HT1A receptor-rich regions, WAY plus prazosin displaced no greater amount than WAY alone.
Conclusions 11C-CUMI-101 has significant binding to alpha-1 adrenoceptors in thalamus of rat and monkey brain. However, in the larger monkey brain, this receptor cross-reactivity was not measureable in regions with moderate to high densities of 5-HT1A receptors.
Research Support The Intramural Research Program of NIMH supported this research (project # Z01-MH-002795-07). We thank PMOD Technologies (Zurich, Switzerland) for providing the image analysis software