Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography

J Med Chem. 2005 Jun 16;48(12):4153-60. doi: 10.1021/jm050155n.

Abstract

In vivo imaging of dopamine D2 receptors with agonist (as opposed to the more commonly employed antagonist) radiotracers could provide important information on the high-affinity (functional) state of the D2 receptor in illnesses such as schizophrenia, movement disorders, and addictions. We report here the radiosynthesis and evaluation of the potent D2 agonist (+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol, (+)-3, labeled with carbon-11, as a potential radiotracer for imaging the high-affinity state of dopamine D2 receptors with positron emission tomography (PET). [(11)C]-(+)-3 was reliably synthesized in the quantities and at the specific activities and radiochemical purities required for human PET studies. Ex vivo biodistribution studies in rat brain demonstrated that [(11)C]-(+)-3 crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer that maps dopamine D2 receptors. The binding of [(11)C]-(+)-3 was saturable and demonstrated an excellent signal-to-noise ratio as measured by its striatum-to-cerebellum ratio of 5.6, 60 min postinjection. The binding was highly stereospecific, and blocking and displacement studies were consistent with selective and specific binding to the dopamine D2 receptors. Further, [(11)C]-(+)-3 showed marked and appropriate sensitivity to both increases and decreases in the levels of endogenous dopamine. Brain radioactive metabolite and physicochemical measurements are in full accord with the desired properties of a neuroreceptor imaging agent for PET. All of the above, coupled with the documented full D2 agonistic properties of (+)-3, strongly indicate that [(11)C]-(+)-3 is a leading candidate radiotracer for the imaging of the dopamine D2 high-affinity state using PET in human subjects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Blood-Brain Barrier / metabolism
  • Carbon Radioisotopes
  • Contrast Media / chemical synthesis*
  • Contrast Media / chemistry
  • Contrast Media / pharmacokinetics
  • Isotope Labeling
  • Male
  • Oxazines / chemical synthesis*
  • Oxazines / chemistry
  • Oxazines / pharmacokinetics
  • Positron-Emission Tomography
  • Protein Binding
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Blood Proteins
  • Carbon Radioisotopes
  • Contrast Media
  • Oxazines
  • Radiopharmaceuticals
  • Receptors, Dopamine D2