title: A second-generation 99m technetium single photon emission computed tomography agent that provides in vivo images of the dopamine transporter in primate brain.
abstract: The dopamine transporter (DAT), located presynaptically on dopamine neurons, provides a marker for Parkinson's disease (Pd) and attention deficit hyperactivity disorder (ADHD). In ADHD, DAT density levels are elevated, while in Pd these levels are depleted. The depletion of DAT levels also corresponds with the loss of dopamine. We now describe the design, synthesis, biology, and SPECT imaging in nonhuman primates of second-generation (99m)technetium-based tropane ligands that bind potently and selectively to the DAT. We demonstrate that improved selectivity and biological stability allows sufficient agent to enter the brain and label the DAT in vivo to provide a quantitative measure of DAT density in nonhuman primates. We introduce FLUORATEC (N-[(2-((3'-N'-propyl-(1"R)-3"alpha-(4-fluorophenyl)tropane-2"beta-1-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]technetium(V) oxide), a DAT imaging agent that has emerged from these studies and is now in phase 1 clinical trials in the U.S.
authors.affiliation: Organix Inc., 240 Salem Street, Woburn, MA 01801, USA. meltzer@organixinc.com
authors.forename: Peter C
authors.initials: PC
authors.lastname: Meltzer
authors.forename: Paul
authors.initials: P
authors.lastname: Blundell
authors.forename: Thomas
authors.initials: T
authors.lastname: Zona
authors.forename: Lihua
authors.initials: L
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.forename: Ali A
authors.initials: AA
authors.lastname: Bonab
authors.forename: Eli
authors.initials: E
authors.lastname: Livni
authors.forename: Alan
authors.initials: A
authors.lastname: Fischman
authors.forename: Bertha K
authors.initials: BK
authors.lastname: Madras
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D066298:In Vitro Techniques; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D015899:Tomography, Emission-Computed, Single-Photon; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C476597:N-((2-((3'-N'-propyl-3''-(4-fluorophenyl)tropane-2'-1-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato)technetium(V) oxide; D009419:Nerve Tissue Proteins; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D014326:Tropanes; D004298:Dopamine