title: Kinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2I.
abstract: 18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β- (4'-methyl-phenyl)nortropane (18F-FE-PE2I) is a novel radioligand for dopamine transporter (DAT) PET. As compared with 11C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane (11C-PE2I), 18F-FE-PE2I shows faster kinetics and more favorable metabolism, with less production of a radiometabolite with intermediate lipophilicity (M1), which-in the case of 11C-PE2I-has been shown to enter the rat brain. In this study, we compared DAT quantification with 11C-PE2I and 18F-FE-PE2I in nonhuman primates, using kinetic and graphical analysis with the input function of both the parent and the radiometabolite, to assess the potential contribution of the radiometabolite.
  
  
  METHODS
  Three rhesus monkeys were examined with 11C-PE2I and 18F-FE-PE2I using the HRRT system. Arterial input functions of the parent and radiometabolite M1 were measured. Kinetic and graphical analyses were applied using either the parent input (methods 1 and 3) or the parent plus radiometabolite input (methods 2 and 4). Outcome measures were distribution volumes (VT and VND), specific-to-nondisplaceable tissue radioactivity ratio at equilibrium (BPND; parent input), and specific-to-nondisplaceable tissue radioactivity ratio at equilibrium in the presence of metabolites (RT; parent plus radiometabolite input).
  
  
  RESULTS
  11C-PE2I showed higher distribution volumes than 18F-FE-PE2I calculated with methods 1 and 3 (striatal VT, ∼300%; VND in cerebellum, ∼30%). With methods 2 and 4, VT in the striatum was approximately 60% higher in the case of 11C-PE2I, whereas no difference in VND was found in the cerebellum. For each radioligand, BPND estimated with methods 1 and 3 tended to be higher than RT estimated with methods 2 and 4. However, the bias of BPND, compared with RT, was much larger for 11C-PE2I (40%-60% in the caudate and putamen) than for 18F-FE-PE2I (<10% in the caudate and putamen).
  
  
  CONCLUSIONS
  The direct comparison between the radioligands confirmed that 18F-FE-PE2I shows faster kinetics and more favorable metabolism than 11C-PE2I. The kinetic and graphical analyses with the input function of the parent and radiometabolite showed that the bias in BPND was much lower for 18F-FE-PE2I than for 11C-PE2I and suggested that the lower production of the radiometabolite M1 would make 18F-FE-PE2I more suitable for the DAT quantification. Further studies in humans are necessary to confirm these findings.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Hospital, Stockholm, Sweden. andrea.varrone@ki.se
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Carsten
authors.initials: C
authors.lastname: Steiger
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takano
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Masanori
authors.initials: M
authors.lastname: Ichise
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis*; D005462:Fluorine Radioisotopes; D007700:Kinetics; D008253:Macaca mulatta; D009662:Nortropanes; D019275:Radiopharmaceuticals
chemical_list: C543996:(E)-N-(3-iodoprop-2-enyl)-2beta-carbofluoroethoxy-3beta-(4'-methyl-phenyl) nortropane; D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes; D019275:Radiopharmaceuticals