@misc{oai:repo.qst.go.jp:00063160,
 author = {Kodaka, Fumitoshi and Ito, Hiroshi and Takano, Harumasa and Takahashi, Hidehiko and Arakawa, Ryosuke and Miyoshi, Michie and Okumura, Masaki and Otsuka, Tatsui and Nakayama, Kazuhiko and Suhara, Tetsuya and 小高 文聰 and 伊藤 浩 and 高野 晴成 and 高橋 英彦 and 荒川 亮介 and 三好 美智恵 and 奥村 正紀 and 大塚 達以 and 須原 哲也},
 month = {Jul},
 note = {Objectives: Early in vitro studies have revealed that dopamine D2 receptors (D2 receptors) have two interconvertible affinity states for endogenous dopamine, referred to as high- and low-affinity state [1]. [C-11]-(R)-2-CH3O-N-n-propylnorapomorphine ([C-11]MNPA), a newly developed D2 receptor agonist ligand, is more sensitive to displacement by endogenous dopamine than [C-11]raclopride in the primate brain[2]. For this reason, [C-11]MNPA represents a promising radioligand for positron emission tomography (PET) imaging of the high-affinity state of the dopamine D2 receptor. Risperidone, which is well known as a serotonin-dopamine antagonist and a commonly prescribed antipsychotic to alleviate positive symptoms of schizophrenia, acts as a full antagonist against dopamine D2 receptors. While the occupancy of dopamine D2 receptors by risperidone has been measured by PET with conventional D2 receptor antagonist ligands such as [C-11]raclopride and [C-11]FLB457, little is known about its pharmacological behavior against the high-affinity state of D2 receptor because those conventional D2 receptor antagonist ligands have affinity to both the high- and low-affinity state of D2 receptor. Here, we measured D2 receptor occupancy of [C-11]MNPA and [C-11]raclopride after oral administration of risperidone to evaluate its pharmacological action against the high-affinity state of D2 receptor.
\nMethods: PET studies were performed on eleven healthy men (21-39 years) under resting condition and oral administration of a single dose of risperidone (0.5-2.0 mg) on separate days. In each condition, PET scans using [C-11]raclopride and [C-11]MNPA were performed sequentially. For each PET study, the binding potentials (BPs) in the striatum were calculated by reference tissue model method with use of the cerebellum as reference region. The occupancy of dopamine D2 receptors was then calculated from the BP values of resting and drug challenge conditions. Relations between dopamine D2 receptor occupancy and the administered dose of risperidone were analyzed for each radioligand.
\nResults: The occupancies of dopamine D2 receptors in [C-11]raclopride and [C-11]MNPA studies ranged from 24% to 70% and from 22% to 66% in the striatum, respectively. The occupancy of [C-11]raclopride was positively correlated with that of [C-11]MNPA (r = 0.72, P = 0.012). The relation between dopamine D2 receptor occupancy and the dose of risperidone (dose-occupancy curve) with [C-11]raclopride and [C-11]MNPA was positive and logarithmically fitted (r = 0.85 for [C-11]raclopride, r = 0.69 for [C-11]MNPA). ED50 values calculated from the dose-occupancy curves with [C-11]raclopride and [C-11]MNPA were 0.98 mg and 1.03 mg, respectively.
\nConclusions: The positive correlation of occupancies between both [C-11]raclopride and [C-11]MNPA studies and similar ED50 values of both studies indicate that risperidone blocks both high- and low-affinity state of dopamine D2 receptors in a similar dose-dependent manner.
\nReferences:
[1] Sibley DR, De Lean A. J Biol Chem 1982; 257(11): 6351-6361.
[2] Seneca N, Finnema SJ. Synapse 2006; 59(5): 260-269., Brain '09 & Brain PET '09},
 title = {EFFECT OF RISPERIDONE ON HIGH-AFFINITY STATE OF DOPAMINE D2 RECEPTOR; A PET STUDY WITH [C-11]MNPA},
 year = {2009}
}