title: Preparation and biological evaluation of iodine-125-IACFT: a selective SPECT agent for imaging dopamine transporter sites.
abstract: Parkinson's disease is a progressive neurodegenerative disorder that is associated with the loss of nerve terminals from specific brain areas, particularly in the caudate and putamen, which contains the highest concentrations of dopamine transporter sites. Previously, we synthesized and evaluated a series of 11C-labeled 2 beta-carbomethoxy -3 beta-aryltropane (WIN 35,428; CFT) derivatives as markers for the dopamine transporter system. These ligands have high affinity and specificity for dopamine transporter sites in vitro and in vivo in laboratory animals. The goal of this study was the preparation and preliminary biological characterization of two new ligands based on the structure of WIN 35,428, the E and Z isomers of N-iodoallyl-2 beta -carbomethoxy-3 beta-(4-fluorophenyl)tropane (E and A IACFT).
  
  
  METHODS
  E and Z IACFT were synthesized and radiolabeled with 125I. The ligands were characterized by in vitro assays of binding to dopamine and serotonin transporters and by autoradiography.
  
  
  RESULTS
  Iodine-125-IACFT was prepared in > 60% radiochemical yield, and > 98% radiochemical purity. Specific activity was 1500 Ci/mmole. In vitro, E-IACFT showed higher affinity for dopamine transporter sites than WIN 35,428 (6.6 versus 11 nM) and better selectivity than RTI-55. The Z isomer was found to have much lower affinity. One hour after an intravenous injection of 125I IACFT in monkeys, ex vivo autoradiographs of the brain revealed high concentrations of tracer in dopamine rich regions such as the caudateputamen. The striatum-to-cerebellum, striatum-to-cortex and striatum-to-thalamus ratios were 10.8, 7.2 and 8.3.
  
  
  CONCLUSIONS
  These result suggest that radiolabeled E-IACFT may be a useful radioligand for SPECT imaging of dopamine transporter sites. IACFT could prove to be extremely useful for the noninvasive evaluation of patients with early Parkinson's disease.
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Elmaleh
authors.forename: A J
authors.initials: AJ
authors.lastname: Fischman
authors.forename: T M
authors.initials: TM
authors.lastname: Shoup
authors.forename: C
authors.initials: C
authors.lastname: Byon
authors.forename: R N
authors.initials: RN
authors.lastname: Hanson
authors.forename: A Y
authors.initials: AY
authors.lastname: Liang
authors.forename: P C
authors.initials: PC
authors.lastname: Meltzer
authors.forename: B K
authors.initials: BK
authors.lastname: Madras
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D015283:Citalopram; D003042:Cocaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010300:Parkinson Disease / Q000000981:diagnostic imaging; D012453:Saimiri; D017367:Selective Serotonin Reuptake Inhibitors; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D002352:Carrier Proteins; D015283:Citalopram; D003042:Cocaine; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C102282:N-iodoallyl-2-carbomethoxy-3-(4-fluorophenyl)tropane; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester