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

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.

Further Characterization of Quinpirole-Elicited Yawning as a Model of Dopamine D3 Receptor Activation in Male and Female Monkeys

“…PET studies were performed on a GE 64 slice PET/CT Discovery VCT scanner (GE Medical Systems, Milwaukee, WI) with an approximate 5-to 6-mm resolution, using the D3R radiotracer [ 11 C]PHNO, synthesized as described in Wilson et al (2005). On the day of the PET study, monkeys (n = 8) were initially anesthetized with 10-15 mg/kg (i.m.)…”

Effects of Oral and Intravenous Administration of Buspirone on Food–Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

“…buspirone in dominant vs. subordinate monkeys may occur because exposure to chronic environmental stress vs. enrichment leads to differential regulation of D2-like receptor subtypes as discussed above. Further pharmacokinetic experiments and brain imaging studies with selective radiotracers (eg, [ 11 C]PHNO, Wilson et al, 2005;Payer et al, 2014) will help to illuminate the mechanisms underlying the observed differences in the behavioral effects of buspirone and other D2-like drugs in dominant and subordinate monkeys.…”

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

“…Radiosynthesis of [ 11 C]-( þ )-PHNO was performed as previously described (Wilson et al, 2005). Each subject was administered B9-10 mCi of tracer (Table 1) and scanned for 90 min.…”