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.

Abstract

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.

• Authors: Mark Slifstein, Raymond F Suckow, Jonathan A Javitch, Thomas Cooper, Jeffrey Lieberman, Anissa Abi-Dargham
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 31 Issue 1 Pg. 293-304 (Jan 2011) ISSN: 1559-7016 [Electronic] United States
• PMID: 20571519 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzazepines
• Dopamine Agonists
• Dopamine Antagonists
• NNC 01-0012
• Phenanthridines
• Radiopharmaceuticals
• Receptors, Dopamine D1
• Receptors, Dopamine D2
• dihydrexidine
• Raclopride

Topics

• Animals
• Benzazepines
• Blood Pressure (drug effects)
• Cerebral Cortex (diagnostic imaging, metabolism)
• Dopamine Agonists (blood, pharmacokinetics)
• Dopamine Antagonists
• Image Processing, Computer-Assisted
• Male
• Papio anubis
• Phenanthridines (pharmacokinetics)
• Positron-Emission Tomography
• Raclopride
• Radiopharmaceuticals
• Receptors, Dopamine D1 (agonists)
• Receptors, Dopamine D2 (metabolism)