title: N-substituted phenyltropanes as in vivo binding ligands for rapid imaging studies of the dopamine transporter.
abstract: Variously substituted phenyltropanes are proven as superb binding ligands for the dopamine transporter (DAT). In this study, we examine four N-substituted phenyltropanes which are derivatives of RTI-55 as in vivo binding ligands in mice. In this series, the methyl group on the nitrogen was replaced by a propyl (RTI-310), an allyl (RTI-311), a butyl (RTI-312), or a fluoropropyl (RTI-313) group. The in vitro binding potencies of these compounds at rat striatal DAT varied somewhat but were about 1 nM. While these compounds did not display marked selectivity for the dopamine transporter, they were more selective than RTI-55. Injection of the radiolabeled compound into mice resulted in striatal-to-cerebellar ratios that varied from about 4.5-6.5. The ratios peaked most rapidly for RTI-311 and RTI-313, at about 20 min. Pharmacological inhibition studies indicated that these compounds were binding to DATs in the striatum, as expected. These findings suggest that some compounds of this type may be excellent in vivo binding ligands for rapid imaging studies of the DAT.
authors.affiliation: Division of Nuclear Medicine and Radiation Health Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2179, USA.
authors.forename: U
authors.initials: U
authors.lastname: Scheffel
authors.forename: J R
authors.initials: JR
authors.lastname: Lever
authors.forename: P
authors.initials: P
authors.lastname: Abraham
authors.forename: K R
authors.initials: KR
authors.lastname: Parham
authors.forename: W B
authors.initials: WB
authors.lastname: Mathews
authors.forename: T
authors.initials: T
authors.lastname: Kopajtic
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
authors.forename: M J
authors.initials: MJ
authors.lastname: Kuhar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000378:metabolism; D003891:Desipramine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D007700:Kinetics; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D027981:Symporters
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; D027981:Symporters; D017374:Paroxetine; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine; D003891:Desipramine