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Neuropsychobiology. 2011;63(3):183-90. doi: 10.1159/000321594. Epub 2011 Feb 8.

P-glycoprotein influence on the brain uptake of a 5-HT(2A) ligand: [(18)F]MH.MZ.

Author information

1
Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany. schmitt@psychiatrie.klinik.uni-mainz.de

Abstract

BACKGROUND/AIMS:

The serotonergic system, especially the 5-HT(2A) receptor, is involved in various diseases and conditions. We have recently developed a new [(18)F]-5-HT(2A) receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [(18)F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT(2A) receptors in vivo. However, [(18)F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier, thus limiting its availability in the central nervous system. The aim of this study was to determine whether transport by P-gp influences the distribution ratio of [(18)F]MH.MZ in the frontal cortex.

METHODS:

The approach was based on P-gp knockout mice which were compared with wild-type mice under several conditions. In vivo pharmacokinetic and microPET investigations were carried out.

RESULTS:

All analyses showed that [(18)F]MH.MZ entered the brain and was sensitive to P-gp transport. In P-gp knockout mice, brain concentrations of MH.MZ were about 5-fold higher than in wild-type animals which is reflected by a 2-fold increase in standardized uptake values of [(18)F]MH.MZ in the frontal cortex of P-gp knockout mice.

CONCLUSION:

Our results give evidence for a functional role of transport mechanisms at the blood-brain barrier, specifically of P-gp, and its subregional distribution. Investigation of these mechanisms will benefit the development of more efficient radioligands and drugs for molecular imaging and pharmacotherapy of the mentally ill.

PMID:
21304228
DOI:
10.1159/000321594
[Indexed for MEDLINE]

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