title: Synthesis and characterization of technetium-99m-labeled tropanes as dopamine transporter-imaging agents.
abstract: In the development of novel Tc-99m-labeled tropane derivatives as dopamine transporter (reuptake site)-imaging agents, a series of neutral and lipophilic complexes containing bis-(aminoethanethiol) as a neutral complexing moiety for a [99mTc]TcO3+ center core was successfully prepared. Biological evaluation of the Tc-99m-labeled complexes 13-16 as central nervous system (CNS) dopamine transporter-imaging agents was reported. Synthesis of the tropane derivatives was achieved by stepwise reactions adding two aminoethanethiol units. The final free thiol ligands were obtained by deblocking the 4-methoxybenzyl protecting group with Hg(OAc)2 to obtain trifluoroacetate salts. All of the Tc-99m complexes, with the exception of 16, displayed good initial brain uptake and selective uptake in the striatal area, where dopamine transporters are concentrated. One of the compounds, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethy] amino]ethanethiolato-(3-)-N2,N2',S2,S2'] oxo-[1R-(exo-exo)]- [99mTc]technetium,[99mTc]TRODAT-1 (13), displayed the highest initial uptake in rat brain (0.4% at 2 min post iv injection); the striatal/cerebellar (ST/ CB) ratio reached 2.8 at 60 min after an iv injection. The specific uptake in rat brain can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; iv, 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.2. In contrast, the specific striatal uptake was not affected by pretreating rats with a noncompeting ligand, haldol (iv, 1 mg/kg). After an iv injection of 9 mCi of [99mTc]TRODAT-1 (13), in vivo images of baboon brain using single-photon emission-computed tomography exhibited excellent localization in striatum (basal ganglia), where dopamine neurons are known to be concentrated. This series of compounds may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS diseases (i.e., Parkinson's disease) in which changes in the dopamine transporter concentration are implicated.
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Meegalla
authors.forename: K
authors.initials: K
authors.lastname: Plössl
authors.forename: M P
authors.initials: MP
authors.lastname: Kung
authors.forename: S
authors.initials: S
authors.lastname: Chumpradit
authors.forename: D A
authors.initials: DA
authors.lastname: Stevenson
authors.forename: S A
authors.initials: SA
authors.lastname: Kushner
authors.forename: W T
authors.initials: WT
authors.lastname: McElgin
authors.forename: P D
authors.initials: PD
authors.lastname: Mozley
authors.forename: H F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000138:chemical synthesis* / Q000737:chemistry; D050483:Dopamine Plasma Membrane Transport Proteins; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D010215:Papio; D051381:Rats; D017207:Rats, Sprague-Dawley; D013667:Technetium; D014018:Tissue Distribution; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014326:Tropanes; D013667:Technetium