Occupancy of dopamine D2 receptors in the mouse brain measured using ultra-high-resolution single-photon emission tomography and [123]IBF.
Functional imaging of small animals, such as mice and rats, using ultra-high-resolution positron emission tomography (PET) and single-photon emission tomography (SPET) should be a valuable tool in studies of drug occupancy of cerebral binding sites. In this study we aimed to demonstrate the feasibility of using ultra-high-resolution SPET to measure the occupancy of dopamine D2 receptors by a competing drug, using the dopamine D2 receptor-specific radioligand iodine-123 5-iodo-7-N-[(1-ethyl-2-pyrrolidinyl) methyl] carboxamido-2,3-dihydrobenzofuran ([123I]IBF). Fourteen normal male mice (CD-1) were jugular vein-cannulated and a bolus infusion protocol was used to deliver 360 MBq [123I]IBF into the mouse (bolus-to-infusion ratio 1.8:1). The mice were scanned using an ultra-high-resolution triple-headed SPET system equipped with pinhole collimators. After sustained equilibrium had been achieved, varying doses of raclopride, a potent dopamine D2 receptor antagonist, were injected through the tail vein and the tracer was allowed to regain equilibrium. A simple equilibrium ratio of striatum to cerebellum provided a measure of D2 receptor binding both before and after injection of raclopride. Following raclopride administration, the system returned to equilibrium with lower specific binding in the striatum, while the counts in the cerebellum were unaffected. Receptor occupancy was 5.2% +/- 2.9% (control), 52.1% +/- 11.1% (0.3 mg/kg), 79.3% +/- 4.8% (1.0 mg/kg), and 94.7% +/- 2.2% (3.0 mg/kg), which gave an ED50=0.26 +/- 0.03 mg/kg using a single receptor site saturation model. This study has demonstrated clearly that ultra-high-resolution SPET of small animals is capable of measuring displacement and occupancy of dopamine D2 receptors by competing ligands.
Acton
Paul D
PD
Department of Radiology, University of Pennsylvania, 3700 Market Street, Room 305, Philadelphia 19104, USA. pacton@sunmac.spect.upenn.edu
Hou
Catherine
C
Kung
Mei-Ping
MP
Plössl
Karl
K
Keeney
Cindy L
CL
Kung
Hank F
HF
D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D005240:Feasibility Studies; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D020891:Raclopride / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
D001572:Benzofurans; D065127:Dopamine D2 Receptor Antagonists; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; C062439:5-iodo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,3-dihydrobenzofurancarboxamide; D020891:Raclopride