In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD.
This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (B(max)) and ligand-transporter affinity (K(d)(app)) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [(11)C]-(+)-alpha-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a B(max) value of 178+/-32 pmol/mL and a K(d)(app) of 47.7+/-9.3 pmol/mL for the non-lesioned side and 30.52+/-5.84 and 43.4+/-15.52 pmol/mL for the lesioned side, respectively. While B(max) was significantly different between the two sides, no significant difference was observed for the K(d)(app). In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinson's disease. A transporter occupancy curve demonstrated negligible transporter occupancy ( approximately 1%) at a specific activity (SA) of 1100 nCi/pmol (assuming an injected dose of 100 microCi/100 g), while 10% occupancy was estimated at 100 nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11%+/-7% for the healthy and 8%+/-12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.
Sossi
Vesna
V
Department of Physics and Astronomy, University of British Columbia, Vancouver, Canada. vesna@physics.ubc.ca
Holden
James E
JE
Topping
Geoffrey J
GJ
Camborde
Marie-Laure
ML
Kornelsen
Rich A
RA
McCormick
Siobhan E
SE
Greene
Jennifer
J
Studenov
Andrei R
AR
Ruth
Thomas J
TJ
Doudet
Doris J
DJ
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D018663:Adrenergic Agents; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; C032811:dihydrotetrabenazine; D016627:Oxidopamine; D013747:Tetrabenazine