title: P-glycoprotein influence on the brain uptake of a 5-HT(2A) ligand: [(18)F]MH.MZ.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany. schmitt@psychiatrie.klinik.uni-mainz.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schmitt
authors.forename: Dianne E
authors.initials: DE
authors.lastname: Lee
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.forename: Markus
authors.initials: M
authors.lastname: Piel
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Buchholz
authors.forename: Frank
authors.initials: F
authors.lastname: Roesch
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Hartmut
authors.initials: H
authors.lastname: Lueddens
authors.forename: Fabian
authors.initials: F
authors.lastname: Debus
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005464:Fluorobenzenes / Q000493:pharmacokinetics*; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; C113334:MDL 105725; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; C079049:volinanserin