Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride.
DAR-0100A, the active enantiomer of dihydrexidine, is a potent dopamine D1 agonist under investigation for treatment of cognitive impairment and negative symptoms of schizophrenia. We measured the dose-occupancy relationship for DAR-0100A at D1 receptors using positron emission tomography (PET) imaging in baboons with [(11)C] NNC112 and its binding to D2 with [(11)C] raclopride. Two baboons were scanned with [(11)C] NNC112 at baseline and after three different doses of DAR-0100A. Two baboons were scanned with [(11)C] raclopride at baseline and after one dose of DAR-0100A. Occupancy (ΔBP(ND)) was computed in the striatum and cortex. A clear relationship was observed between plasma concentration of DAR-0100A and ΔBP(ND). ΔBP(ND) was larger in the striatum than in the cortex, consistent with reports showing that 25% of [(11)C] NNC112 BP(ND) in the cortex is attributed to 5-HT(2A). Plasma EC(50) estimates ranged from 150 to 550 ng/mL according to the constraints on the model. There was no detectable effect of DAR-0100A on [(11)C] raclopride BP(ND). These data suggest that at doses likely to be administered to patients, occupancy will not be detectable with [(11)C] NNC112 PET and binding of DAR-0100A to D2 will be negligible. This is the first demonstration with PET of a significant occupancy by a full D1 agonist in vivo.
Slifstein
Mark
M
Department of Psychiatry, Columbia University, New York, New York, USA. mms218@columbia.edu
Suckow
Raymond F
RF
Javitch
Jonathan A
JA
Cooper
Thomas
T
Lieberman
Jeffrey
J
Abi-Dargham
Anissa
A
D000818:Animals; D001552:Benzazepines; D001794:Blood Pressure / Q000187:drug effects; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000378:metabolism*; D018491:Dopamine Agonists / Q000097:blood / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists; D007091:Image Processing, Computer-Assisted; D008297:Male; D048530:Papio anubis; D010617:Phenanthridines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D020891:Raclopride; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000378:metabolism
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C114704:NNC 01-0012; D010617:Phenanthridines; D019275:Radiopharmaceuticals; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C061532:dihydrexidine; D020891:Raclopride