title: [¹⁸F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT₂A receptor densities in the rat brain.
abstract: BACKGROUND
  The selective 5-hydroxytryptamine type 2a receptor (5-HT(2A)R) radiotracer [(18)F]altanserin is a promising ligand for in vivo brain imaging in rodents. However, [(18)F]altanserin is a substrate of P-glycoprotein (P-gp) in rats. Its applicability might therefore be constrained by both a differential expression of P-gp under pathological conditions, e.g. epilepsy, and its relatively low cerebral uptake. The aim of the present study was therefore twofold: (i) to investigate whether inhibition of multidrug transporters (MDT) is suitable to enhance the cerebral uptake of [(18)F]altanserin in vivo and (ii) to test different pharmacokinetic, particularly reference tissue-based models for exact quantification of 5-HT(2A)R densities in the rat brain.
  
  
  METHODS
  Eighteen Sprague-Dawley rats, either treated with the MDT inhibitor cyclosporine A (CsA, 50 mg/kg, n=8) or vehicle (n=10) underwent 180-min PET scans with arterial blood sampling. Kinetic analyses of tissue time-activity curves (TACs) were performed to validate invasive and non-invasive pharmacokinetic models.
  
  
  RESULTS
  CsA application lead to a two- to threefold increase of [(18)F]altanserin uptake in different brain regions and showed a trend toward higher binding potentials (BP(ND)) of the radioligand.
  
  
  CONCLUSIONS
  MDT inhibition led to an increased cerebral uptake of [(18)F]altanserin but did not improve the reliability of BP(ND) as a non-invasive estimate of 5-HT(2A)R. This finding is most probable caused by the heterogeneous distribution of P-gp in the rat brain and its incomplete blockade in the reference region (cerebellum). Differential MDT expressions in experimental animal models or pathological conditions are therefore likely to influence the applicability of imaging protocols and have to be carefully evaluated.
authors.affiliation: Institute of Neuroscience and Medicine, INM-2, Forschungszentrum Jülich GmbH, Jülich, Germany. Electronic address: t.kroll@fz-juelich.de.
authors.forename: Tina
authors.initials: T
authors.lastname: Kroll
authors.forename: David
authors.initials: D
authors.lastname: Elmenhorst
authors.forename: Andreas
authors.initials: A
authors.lastname: Matusch
authors.forename: A Avdo
authors.initials: AA
authors.lastname: Celik
authors.forename: Franziska
authors.initials: F
authors.lastname: Wedekind
authors.forename: Angela
authors.initials: A
authors.lastname: Weisshaupt
authors.forename: Simone
authors.initials: S
authors.lastname: Beer
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D007650:Ketanserin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D008024:Ligands; D049268:Positron-Emission Tomography; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005462:Fluorine Radioisotopes; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; C071983:altanserin; D016572:Cyclosporine; D007650:Ketanserin
keywords: 5-HT(2A)R; Kinetic modeling; Positron emission tomography; Rat; Transmembrane efflux transporters; [(18)F]Altanserin