6533b820fe1ef96bd1279177

RESEARCH PRODUCT

P-Glycoprotein Influence on the Brain Uptake of a 5-HT2A Ligand: [18F]MH.MZ

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<i>Background/Aims:</i> The serotonergic system, especially the 5-HT<sub>2A</sub> receptor, is involved in various diseases and conditions. We have recently developed a new [<sup>18</sup>F]-5-HT<sub>2A</sub> receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [<sup>18</sup>F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT<sub>2A</sub> receptors in vivo. However, [<sup>18</sup>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 [<sup>18</sup>F]MH.MZ in the frontal cortex. <i>Methods:</i> 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. <i>Results:</i> All analyses showed that [<sup>18</sup>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 [<sup>18</sup>F]MH.MZ in the frontal cortex of P-gp knockout mice. <i>Conclusion:</i> 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.