title: [123I]epidepride binding to cerebellar dopamine D2/D3 receptors is displaceable: implications for the use of cerebellum as a reference region.
abstract: The low density of cerebellar dopamine D(2)/D(3) receptors provides the basis for using the cerebellum as a representation of free- and non-specifically bound radioligand in positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies. With the development of ultra high-affinity dopamine D(2)/D(3) ligands like [(123)I]epidepride, [(18)F]fallypride, and [(11)C]FLB-457, quantification of extrastriatal low density receptor populations including the cerebellum is possible with important implications for calculation of binding parameters. [(123)I]epidepride-SPECT was performed in 23 patients with schizophrenia before and after 3 months of antipsychotic treatment with either risperidone (n=14) or zuclopenthixol (n=9). In the unblocked situation and partially blocked situation, the average distribution volumes were 5.2+/-1.3 mL/mL and 4.0+/-0.8 mL/mL, respectively. The paired distribution volumes were reduced by 22+/-15% (mean+/-SD) after antipsychotic treatment (p<0.0001, paired Student's t-test). From the paired distribution volumes in cerebellum and extrastriatal regions, the average distribution volume representing free and non-specifically bound [(123)I]epidepride was calculated to be 3.3+/-0.8 mL/mL. Both the % [(123)I]epidepride fraction of plasma radioactivity (p>0.76) and the plasma [(123)I]epidepride concentration (p>0.45) were unchanged after antipsychotic treatment (paired Student's t-test). These results strongly suggest the presence of "non-negligible" specific [(123)I]epidepride binding to dopamine D(2)/D(3) receptors in the cerebellum. Using the cerebellum as a representation of free and non-specifically bound radioligand and neglecting the specifically bound component may lead to results that erroneously imply that antipsychotic drugs bind to extrastriatal dopamine D(2)/D(3) receptors with a higher affinity than to striatal dopamine D(2)/D(3) receptors.
authors.affiliation: Neurobiology Research Unit, University of Copenhagen, N9201, Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. pinborg@nru.dk
authors.forename: Lars H
authors.initials: LH
authors.lastname: Pinborg
authors.forename: Charlotte
authors.initials: C
authors.lastname: Videbaek
authors.forename: Morten
authors.initials: M
authors.lastname: Ziebell
authors.forename: Torben
authors.initials: T
authors.lastname: Mackeprang
authors.forename: Lars
authors.initials: L
authors.lastname: Friberg
authors.forename: Hans
authors.initials: H
authors.lastname: Rasmussen
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Birte Y
authors.initials: BY
authors.lastname: Glenthoj
mesh_terms: D000328:Adult; D001549:Benzamides / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D011859:Radiography; D011869:Radioligand Assay / Q000379:methods; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D012016:Reference Values; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D001549:Benzamides; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C063525:epidepride