title: [(11)C, (127)I] Altropane: a highly selective ligand for PET imaging of dopamine transporter sites.
abstract: The E isomer of (123)I-2beta-carbomethoxy-3beta-(4-fluorophenyl)-N-(1-iodoprop-1-en-3-yl)nortropane (Altropane(R)) shows high affinity (IC(50) = 6.62 +/- 0.78 nmol) and selectivity (DA/5-HT = 25) for DAT sites in the striatum. Recently, dynamic SPECT studies in healthy volunteers and patients with Parkinson disease demonstrated that the kinetics of striatal accumulation followed a pattern that is characteristic of a reversible tracer with maximal accumulation within 30 min after injection. These findings suggested that radiolabeling Altropane with [(11)C] might provide an equivalent and complementary tracer for PET studies. [(127)I] Altropane was treated with HCl to hydrolyze the methyl ester bond and yield a precursor for [(11)C] labeling. Introduction of an [(11)C] methyl ester group was achieved by treatment with [(11)C] CH(3)I followed by HPLC purification. Five healthy rhesus monkeys were injected with approximately 10 mCi of [(127)I,(11)C] Altropane and dynamic PET images were acquired over 90 min. Arterial blood samples were collected in parallel with imaging and metabolite analysis was performed by HPLC. The PET and metabolite corrected arterial blood data were to calculate k(3)/k(4) by two methods: 1) nonlinear least-squares fitting, and 2) a linear graphical method for reversible ligands. The synthetic procedure yielded high specific activity tracer, >1,000 mCi/micro mole, with radiochemical purity >95%. Synthesis time was approximately 30 min. The PET images revealed excellent striatal definition, with clear separation of caudate nucleus and putamen and minimal accumulation in brain regions with high 5HT transporter density. Metabolite analysis demonstrated that at 60 min after injection, approximately 80% of circulating tracer was intact [(127)I,(11)C] Altropane and the remainder was converted to polar metabolites. Values for k(3)/k(4) calculated by two analysis methods were remarkably similar: Method 1, 3.48 +/- 0.41; Method 2, 3.77 +/- 0.45 (mean +/- SEM, t = 2.31, df = 8, P = 0.64). These results establish that Altropane has the important characteristics of: 1) rapid and specific striatal binding; 2) high selectivity for DA vs. 5-HT transporter sites; 3) reversible binding kinetics; 4) potential for multiple injection studies; 5) high efficiency labeling with either [(11)C] or [(123)I]; 6) applicability for both PET and SPECT. These properties make Altropane an important DAT ligand for both research and clinical applications.
authors.affiliation: Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA. fischman@petw6.mgh.harvard.edu
authors.forename: A J
authors.initials: AJ
authors.lastname: Fischman
authors.forename: A A
authors.initials: AA
authors.lastname: Bonab
authors.forename: J W
authors.initials: JW
authors.lastname: Babich
authors.forename: E
authors.initials: E
authors.lastname: Livni
authors.forename: N M
authors.initials: NM
authors.lastname: Alpert
authors.forename: P C
authors.initials: PC
authors.lastname: Meltzer
authors.forename: B K
authors.initials: BK
authors.lastname: Madras
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000032:analysis*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics; D004298:Dopamine / Q000032:analysis; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D007700:Kinetics; D008024:Ligands; D008253:Macaca mulatta; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012680:Sensitivity and Specificity; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C102282:N-iodoallyl-2-carbomethoxy-3-(4-fluorophenyl)tropane; D009419:Nerve Tissue Proteins; D003042:Cocaine; D004298:Dopamine