Evaluation of [11C]-(+)-PHNO as an agonist radiotracer for imaging high-affinity dopamine D2 receptors

Abstract

In vivo imaging of dopamine D2 receptors with agonists, 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 or Movement Disorders. We report here our evaluation of the potent dopamine D2 agonist, [11C]-(+)-PHNO, as a potential radiotracer for imaging the high affinity state of D2 receptors with positron emission tomography (PET). Ex vivo biodistribution studies in rat brain demonstrated that [11C]-(+)-PHNO crossed the blood-brain barrier readily and had an appropriate regional brain distribution for a radiotracer which maps dopamine D2 receptors. [11C]-(+)-PHNO binding was saturable and demonstrated excellent signal to noise as measured by its striatum to cerebellum ratio of 5.4 at 60 min post-injection (Fig. 1). D2 binding was highly stereospecific; the inactive enantiomer [11C]-(-)-PHNO displayed no preferential regional uptake. Blocking and displacement studies were consistent with reversible, selective, and specific binding to the dopamine D2 receptors. Pre-administration of haloperidol or raclopride (0.5 mg/kg i.v. or s.c.) reduced specific binding by >90% while the D1 selective antagonist, SCH 23390, had no effect. -Microprobe experiments with [11C]-(+)-PHNO also demonstrated high specific binding of [11C]-(+)-PHNO in rat striatum in vivo and allowed the determination of a binding potential for [11C]-(+)-PHNO in the striatum of 2.4 (Fig. 2). Physico-chemical measurements (e.g. Log D of 2.140.02; n=12) and brain radioactive metabolite measurements were 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 (+)-PHNO, strongly indicate that [11C]-(+)-PHNO is a leading candidate radiotracer for the imaging of the dopamine D2 high affinity state using PET.