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

J Cereb Blood Flow Metab. 2011 Jan;31(1):293-304. doi: 10.1038/jcbfm.2010.91. Epub 2010 Jun 23.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzazepines*
  • Blood Pressure / drug effects
  • Cerebral Cortex / diagnostic imaging*
  • Cerebral Cortex / metabolism*
  • Dopamine Agonists / blood
  • Dopamine Agonists / 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

Substances

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