title: In vivo dopamine transporter imaging in a unilateral 6-hydroxydopamine rat model of Parkinson disease using 11C-methylphenidate PET.
abstract: Dopamine transporter (DAT) function is altered by many neurodegenerative diseases. For instance, in Parkinson disease DAT density has been shown to decrease in early disease and to play a role in the occurrence of motor complications. DAT is thus an important imaging target with potential therapeutic relevance in humans and animal models of disease. The PET DAT marker (11)C-methylphenidate is commonly used to quantify DAT function. Here we investigate the characteristics of the (11)C-methylphenidate-derived quantification of DAT in rodents using the 6-hydroxydopamine Parkinson disease rat model.
  
  
  METHODS
  Seven unilaterally 6-hydroxydopamine-lesioned rats (dopaminergic denervation [DD] range, 36%-94%) were injected with 3.7 MBq/100 g of body weight and tracer masses ranging from 93.8 to 0.0041 μg/100 g of body weight. We evaluated the maximum available transporter density and the in vivo (apparent) ligand-transporter dissociation constant (B(max) and K app d, respectively) with an in vivo Scatchard method using several modeling approaches and estimated the transporter occupancy as a function of the amount of tracer injected and tracer specific activity (SA).
  
  
  RESULTS
  Strong evidence of different nonspecific binding in the striatal region, compared with the reference region, leading to bias in the estimate of DD severity was found. One percent transporter occupancy was reached with 0.14 μg of tracer/100 g of body weight, corresponding to an SA of 5.7 kBq/pmol for the given radioactivity dose, and 10% occupancy was reached at 1.5 μg of tracer/100 g of body weight, corresponding to an SA of 0.57 kBq/pmol. The 6-hydroxydopamine lesion affected B(max) (control, 402 ± 94 pmol/mL; lesioned, 117 ± 120 pmol/mL; P = 0.003) but not K app d (control, 331 ± 63 pmol/mL; lesioned, 362 ± 119 pmol/mL; P = 0.63).
  
  
  CONCLUSIONS
  Although DAT imaging can be performed at a relatively high mass of (11)C-methylphenidate (low SA), the additional nonspecific binding found in the striatum can introduce a DD severity-dependent bias in the estimate of tissue-derived binding potential and care must be taken in comparing (11)C-methylphenidate-derived assessment of DD with that obtained using other dopaminergic tracers.
authors.affiliation: Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia, Canada. vesna@physics.ubc.ca
authors.forename: Vesna
authors.initials: V
authors.lastname: Sossi
authors.forename: Katherine
authors.initials: K
authors.lastname: Dinelle
authors.forename: Salma
authors.initials: S
authors.lastname: Jivan
authors.forename: Kristina
authors.initials: K
authors.lastname: Fischer
authors.forename: James E
authors.initials: JE
authors.lastname: Holden
authors.forename: Doris
authors.initials: D
authors.lastname: Doudet
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D008297:Male; D008774:Methylphenidate; D016627:Oxidopamine; D010300:Parkinson Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D008774:Methylphenidate; D016627:Oxidopamine