TY - JOUR

T1 - Evaluation of the novel 5-HT4 receptor PET ligand [11C]SB207145 in the Göttingen minipig

AU - Kornum, Birgitte R

AU - Lind, Nanna M

AU - Gillings, Nic

AU - Marner, Lisbeth

AU - Andersen, Flemming

AU - Knudsen, Gitte M

PY - 2009/1/1

Y1 - 2009/1/1

N2 - This study investigates 5-hydroxytryptamine 4 (5-HT(4)) receptor binding in the minipig brain with positron emission tomography (PET), tissue homogenate-binding assays, and autoradiography in vitro. The cerebral uptake and binding of the novel 5-HT(4) receptor radioligand [(11)C]SB207145 in vivo was modelled and the outcome compared with postmortem receptor binding. Different models for quantification of [(11)C]SB207145 binding were evaluated: One-tissue and two-tissue compartment kinetic modelling, Logan arterial input, and three different reference tissue models. We report that the pig autoradiographic 5-HT(4) receptor distribution resembles the human 5-HT(4) receptor distribution with the highest binding in the striatum and no detectable binding in the cerebellum. We found that in the minipig brain [(11)C]SB207145 follows one-tissue compartment kinetics, and the simplified reference tissue model provides stable and precise estimates of the binding potential in all regions. The binding potentials calculated for striatum, midbrain, and cortex from the PET data were highly correlated with 5-HT(4) receptor concentrations determined in brain homogenates from the same regions, except for hippocampus where PET-measurements significantly underestimate the 5-HT(4) receptor binding, probably because of partial volume effects. This study validates the use of [(11)C]SB207145 as a promising PET radioligand for in vivo brain imaging of the 5-HT(4) receptor in humans.

AB - This study investigates 5-hydroxytryptamine 4 (5-HT(4)) receptor binding in the minipig brain with positron emission tomography (PET), tissue homogenate-binding assays, and autoradiography in vitro. The cerebral uptake and binding of the novel 5-HT(4) receptor radioligand [(11)C]SB207145 in vivo was modelled and the outcome compared with postmortem receptor binding. Different models for quantification of [(11)C]SB207145 binding were evaluated: One-tissue and two-tissue compartment kinetic modelling, Logan arterial input, and three different reference tissue models. We report that the pig autoradiographic 5-HT(4) receptor distribution resembles the human 5-HT(4) receptor distribution with the highest binding in the striatum and no detectable binding in the cerebellum. We found that in the minipig brain [(11)C]SB207145 follows one-tissue compartment kinetics, and the simplified reference tissue model provides stable and precise estimates of the binding potential in all regions. The binding potentials calculated for striatum, midbrain, and cortex from the PET data were highly correlated with 5-HT(4) receptor concentrations determined in brain homogenates from the same regions, except for hippocampus where PET-measurements significantly underestimate the 5-HT(4) receptor binding, probably because of partial volume effects. This study validates the use of [(11)C]SB207145 as a promising PET radioligand for in vivo brain imaging of the 5-HT(4) receptor in humans.

KW - Animals

KW - Autoradiography

KW - Brain

KW - Carbon Radioisotopes

KW - Kinetics

KW - Ligands

KW - Piperidines

KW - Positron-Emission Tomography

KW - Receptors, Serotonin, 5-HT4

KW - Swine

KW - Swine, Miniature

U2 - 10.1038/jcbfm.2008.110

DO - 10.1038/jcbfm.2008.110

M3 - Journal article

C2 - 18797470

VL - 29

SP - 186

EP - 196

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 1

ER -