Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

TY - JOUR

T1 - Brain imaging of serotonin 4 receptors in humans with [11C]SB207145-PET

AU - Marner, Lisbeth

AU - Gillings, Nic

AU - Madsen, Karine

AU - Erritzoe, David

AU - Baaré, William F C

AU - Svarer, Claus

AU - Hasselbalch, Steen G

AU - Knudsen, Gitte M

N1 - Copyright 2010 Elsevier Inc. All rights reserved.

PY - 2010/4/15

Y1 - 2010/4/15

N2 - Pharmacological stimulation of the serotonin 4 (5-HT(4)) receptor has shown promise for treatment of Alzheimer's disease and major depression. A new selective radioligand, [(11)C]SB207145, for positron emission tomography (PET) was used to quantify brain 5-HT(4) receptors in sixteen healthy subjects (20-45 years, 8 males) using the simplified reference tissue model. We tested within our population the effect of age and other demographic factors on the endpoint. In seven subjects, we tested the vulnerability of radioligand binding to a pharmacolological challenge with citalopram, which is expected to increase competition from endogenous serotonin. Given radiotracer administration at a range of specific activities, we were able to use the individual BP(ND) measurements for population-based estimation of the saturation binding parameters; B(max) ranged from 0.3 to 1.6 nM. B(max) was in accordance with post-mortem brain studies (Spearman's r=0.83, p=0.04), and the regional binding potentials, BP(ND), were on average 2.6 in striatum, 0.42 in prefrontal cortex, and 0.91 in hippocampus. We found no effect of sex but a decreased binding with age (p=0.046). A power analysis showed that, given the low inter-and intrasubject variation, use of the present method will enable detection of a 15% difference in striatum with only 7-13 subjects in a 2-sample test and with only 4-5 subjects in a paired test. The citalopram challenge did not discernibly alter [(11)C]SB207145 binding. In conclusion, the 5-HT(4) receptor binding in human brain can be reliably assessed with [(11)C]SB207145, which is encouraging for future PET studies of drug occupancy or patients with neuropsychiatric disorders.

AB - Pharmacological stimulation of the serotonin 4 (5-HT(4)) receptor has shown promise for treatment of Alzheimer's disease and major depression. A new selective radioligand, [(11)C]SB207145, for positron emission tomography (PET) was used to quantify brain 5-HT(4) receptors in sixteen healthy subjects (20-45 years, 8 males) using the simplified reference tissue model. We tested within our population the effect of age and other demographic factors on the endpoint. In seven subjects, we tested the vulnerability of radioligand binding to a pharmacolological challenge with citalopram, which is expected to increase competition from endogenous serotonin. Given radiotracer administration at a range of specific activities, we were able to use the individual BP(ND) measurements for population-based estimation of the saturation binding parameters; B(max) ranged from 0.3 to 1.6 nM. B(max) was in accordance with post-mortem brain studies (Spearman's r=0.83, p=0.04), and the regional binding potentials, BP(ND), were on average 2.6 in striatum, 0.42 in prefrontal cortex, and 0.91 in hippocampus. We found no effect of sex but a decreased binding with age (p=0.046). A power analysis showed that, given the low inter-and intrasubject variation, use of the present method will enable detection of a 15% difference in striatum with only 7-13 subjects in a 2-sample test and with only 4-5 subjects in a paired test. The citalopram challenge did not discernibly alter [(11)C]SB207145 binding. In conclusion, the 5-HT(4) receptor binding in human brain can be reliably assessed with [(11)C]SB207145, which is encouraging for future PET studies of drug occupancy or patients with neuropsychiatric disorders.

KW - Adult

KW - Aging

KW - Brain

KW - Brain Mapping

KW - Citalopram

KW - Corpus Striatum

KW - Female

KW - Hippocampus

KW - Humans

KW - Male

KW - Middle Aged

KW - Piperidines

KW - Positron-Emission Tomography

KW - Prefrontal Cortex

KW - Receptors, Serotonin, 5-HT4

KW - Serotonin Uptake Inhibitors

KW - Sex Characteristics

KW - Young Adult

U2 - 10.1016/j.neuroimage.2010.01.054

DO - 10.1016/j.neuroimage.2010.01.054

M3 - Journal article

C2 - 20096787

SN - 1053-8119

VL - 50

SP - 855

EP - 861

JO - NeuroImage

JF - NeuroImage

IS - 3

ER -