Binding characteristics and sensitivity to endogenous dopamine of [11C]-(+)-PHNO, a new agonist radiotracer for imaging the high-affinity state of D2 receptors in vivo using positron emission tomography

J Neurochem. 2006 May;97(4):1089-103. doi: 10.1111/j.1471-4159.2006.03840.x. Epub 2006 Apr 5.


[11C]-(+)-PHNO (4-propyl-9-hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high-affinity states of the D2 receptors (D2-high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [11C]-(+)-PHNO and compare it with the well characterized antagonist D2 radioligand, [11C]raclopride, in cat. [11C]-(+)-PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 +/- 0.85. Pre-treatment with specific D1 (SCH23390), D2 (raclopride, haloperidol) and D3 receptor (SB-277011) antagonists indicated that [11C]-(+)-PHNO binding in striatum is specific to D2 receptors. Within-subject comparisons showed that [11C]-(+)-PHNO BP in striatum was almost 2.5-fold higher than that measured with [11C]-(-)-NPA ([11C]-(-)-N-propyl-norapomorphine). Comparison of the dose-effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [11C]-(+)-PHNO was more sensitive to the dopamine releasing effect of amphetamine than [11C]raclopride. Amphetamine induced up to 83 +/- 4% inhibition of [11C]-(+)-PHNO BP and only up to 56 +/- 8% inhibition of [11C]raclopride BP. Scatchard analyses of [11C]-(+)-PHNO and [11C]raclopride bindings in two cats showed that the Bmax obtained with the agonist (29.6 and 32.9 pmol/mL) equalled that obtained with the antagonist (30.6 and 33.4 pmol/mL). The high penetration of [11C]-(+)-PHNO in brain, its high signal-to-noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [11C]-(+)-PHNO has highly suitable characteristics for probing the D2-high with PET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Binding Sites / physiology
  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Brain / diagnostic imaging*
  • Brain / metabolism*
  • Brain Chemistry / drug effects
  • Brain Chemistry / physiology
  • Carbon Radioisotopes / metabolism
  • Cats
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Dopamine Agonists / metabolism
  • Dopamine Agonists / pharmacokinetics
  • Dopamine Antagonists / metabolism
  • Dopamine Antagonists / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Male
  • Oxazines / metabolism*
  • Oxazines / pharmacokinetics
  • Positron-Emission Tomography / methods*
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism
  • Raclopride / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology


  • Carbon Radioisotopes
  • Dopamine Agonists
  • Dopamine Antagonists
  • Oxazines
  • Receptors, Dopamine D2
  • naxagolide
  • Raclopride
  • Amphetamine
  • Dopamine