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

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 [¹⁸F]-5-HT_2A receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [¹⁸F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT_2A receptors in vivo. However, [¹⁸F]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 [¹⁸F]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 [¹⁸F]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 [¹⁸F]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.

Blocking of efflux transporters in rats improves translational validation of brain radioligands

“…Substrates of P-gp are pumped out into the lumen of the brain capillaries and thus removed from the brain tissue [7]. P-gp activity is known to be a major factor limiting the brain uptake of PET tracers in rodents [8,9]. If tracers for central nervous system (CNS) targets are initially evaluated in rodents and show low brain uptake, they could be de-selected for further translation, even though they would have worked in higher species, including humans.…”