Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

TY - JOUR

T1 - Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

AU - Palner, Mikael

AU - Underwood, Mark D

AU - Kumar, Dileep J S

AU - Arango, Victoria

AU - Knudsen, Gitte M

AU - John Mann, J

AU - Parsey, Ramin V

N1 - Copyright © 2011 Wiley-Liss, Inc.

PY - 2011/8

Y1 - 2011/8

N2 - [3H]CUMI-101 is a 5-HT1A partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [3H]CUMI-101 ex vivo in awake rats and determine if [3H]CUMI-101 can measure changes in synaptic levels of serotonin after different challenge paradigms. [3H]CUMI-101 shows good uptake and good specific binding ratio (SBR) in frontal cortex 5.18 and in hippocampus 3.18. Binding was inhibited in a one-binding-site fashion by WAY100635 and unlabeled CUMI-101. The ex vivo Bmax of [3H]CUMI-101 in frontal cortex (98.7 fmol/mg) and hippocampus (131 fmol/kg) agree with the ex vivo Bmax of [3H]MPPF in frontal cortex (147.1 fmol/mg) and hippocampus (72.1 fmol/mg) and with in vitro values reported with 8-OH-DPAT. Challenges with citalopram, a selective serotonin reuptake inhibitor, fenfluramine, a serotonin releaser, and 4-chloro-DL-phenylalanine, a serotonin synthesis inhibitor, did not show any effect on the standardized uptake values (SUVs) in any region. Citalopram did alter SBR, but this was due to changes in cerebellar SUVs. Our results indicate that [3H]CUMI-101 is a good radioligand for imaging 5-HT1A high-density regions in rats; however, the results from pharmacological challenges remain inconclusive.

AB - [3H]CUMI-101 is a 5-HT1A partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [3H]CUMI-101 ex vivo in awake rats and determine if [3H]CUMI-101 can measure changes in synaptic levels of serotonin after different challenge paradigms. [3H]CUMI-101 shows good uptake and good specific binding ratio (SBR) in frontal cortex 5.18 and in hippocampus 3.18. Binding was inhibited in a one-binding-site fashion by WAY100635 and unlabeled CUMI-101. The ex vivo Bmax of [3H]CUMI-101 in frontal cortex (98.7 fmol/mg) and hippocampus (131 fmol/kg) agree with the ex vivo Bmax of [3H]MPPF in frontal cortex (147.1 fmol/mg) and hippocampus (72.1 fmol/mg) and with in vitro values reported with 8-OH-DPAT. Challenges with citalopram, a selective serotonin reuptake inhibitor, fenfluramine, a serotonin releaser, and 4-chloro-DL-phenylalanine, a serotonin synthesis inhibitor, did not show any effect on the standardized uptake values (SUVs) in any region. Citalopram did alter SBR, but this was due to changes in cerebellar SUVs. Our results indicate that [3H]CUMI-101 is a good radioligand for imaging 5-HT1A high-density regions in rats; however, the results from pharmacological challenges remain inconclusive.

U2 - 10.1002/syn.20888

DO - 10.1002/syn.20888

M3 - Journal article

SN - 0887-4476

VL - 65

SP - 715

EP - 723

JO - Synapse

JF - Synapse

IS - 8

ER -