title: Imaging of the striatal and extrastriatal dopamine transporter with (18)F-LBT-999: quantification, biodistribution, and radiation dosimetry in nonhuman primates.
abstract: The aim of this study was to evaluate the quantification, biodistribution, and radiation dosimetry of the novel dopamine transporter (DAT) radioligand (18)F-(2S,3S)-methyl 8-((E)-4-fluorobut-2-en-1-yl)-3-(p-tolyl)-8-azabicyclo[3.2.1]octane-2-carboxylate ((18)F-LBT-999) in nonhuman primates.
  
  
  METHODS
  The brain study was conducted in 4 female rhesus monkeys. PET measurements were conducted for 243 min using the high-resolution research tomograph (HRRT) with the measurement of the metabolite-corrected arterial input function and protein binding. Quantification was performed with kinetic analysis using 2-tissue- and 1-tissue-compartment models, with Logan graphical analysis and with different reference tissue models. The outcome measures were total distribution volume (V(T)), nondisplaceable distribution volume (V(ND)), binding potential relative to the free concentration of radioligand in plasma (BP(F)), and binding potential relative to the concentration of nondisplaceable radioligand in tissue (BP(ND)) = V(T) - V(ND)/V(ND) using the cerebellum as a reference region. For the biodistribution and radiation dosimetry, 2 female cynomolgus monkeys were studied. Whole-body PET scans were obtained using a PET/CT system for approximately 250 min. Estimates of the absorbed radiation dose in humans were calculated using OLINDA/EXM software.
  
  
  RESULTS
  (18)F-LBT-999 showed good brain uptake (300% standardized uptake value) and regional distribution according to known DAT density. The 2-tissue-compartment model was the preferred model for the quantification. Late peak equilibrium (120-140 min) and slow washout were observed in the striatum, with high variability of V(T), BP(F), and BP(ND). When the different models were compared with the 2-tissue-compartment model, the underestimation of V(T) or BP(ND) was larger in the caudate and putamen than in the midbrain and thalamus. The reference tissue models were suitable for the quantification. The whole-body distribution study showed that the main routes of excretion of (18)F-LBT-999 were the urinary and gastrointestinal systems, with the bladder being the critical organ. Accumulation of (18)F-LBT-999 was found in the bone and skull, with a relatively high dose estimated for the osteogenic cells. The range of calculated effective dose was 0.021-0.022 mSv/MBq.
  
  
  CONCLUSIONS
  (18)F-LBT-999 seemed to be a suitable PET radioligand for the DAT quantification, particularly for extrastriatal regions. The skull uptake did not seem to be a limitation for brain imaging. The calculated dosimetry estimates based on data in nonhuman primates seemed comparable with those of other clinically used (18)F-labeled radioligands, for example, (18)F-FDG (0.024-0.027 mSv/MBq).
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden. andrea.varrone@ki.se
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Vladimir
authors.initials: V
authors.lastname: Stepanov
authors.forename: Ryuji
authors.initials: R
authors.lastname: Nakao
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Balázs
authors.initials: B
authors.lastname: Gulyás
authors.forename: Patrik
authors.initials: P
authors.lastname: Emond
authors.forename: Jean Bernard
authors.initials: JB
authors.lastname: Deloye
authors.forename: Johnny
authors.initials: J
authors.lastname: Vercouillie
authors.forename: Michael G
authors.initials: MG
authors.lastname: Stabin
authors.forename: Cathrine
authors.initials: C
authors.lastname: Jonsson
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003342:Corpus Striatum / Q000473:pathology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes / Q000494:pharmacology; D008253:Macaca mulatta; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D011868:Radioisotopes / Q000494:pharmacology; D011874:Radiometry / Q000379:methods*; D013788:Thalamus / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed / Q000379:methods; D016896:Treatment Outcome
chemical_list: C508666:8-((E)-4-fluoro-but-2-enyl)-3beta-p-tolyl-8-aza-bicyclo(3.2.1)octane-2beta-carboxylic acid methyl ester; D050483:Dopamine Plasma Membrane Transport Proteins; D005462:Fluorine Radioisotopes; D011868:Radioisotopes; D003042:Cocaine