High-Affinity States of Human Brain Dopamine D2/3 Receptors Imaged by the Agonist [11C]-(+)-PHNO

Background The high-affinity states of dopamine D2-receptors (D2high) are postulated to be functionally responsible for signal transduction. At present, no useful in vivo method exists to selectively measure D2high in humans, as current D2 radioligands for positron emission tomography (PET) are either not D2-selective or do not differentiate between D2 high- and low-affinity states. Methods The D2-agonist (+)-PHNO [(+)4-propyl-9-hydroxynaphthoxazine] was labeled with carbon-11 and studied with PET. Eight [11C]-(+)-PHNO scans were acquired in four healthy volunteers. Results We observed greatest [11C]-(+)-PHNO accumulation in caudate, putamen, and globus pallidus [binding potentials (BPs): 3.00 ± .4, 3.10 ± .2, and 4.17 ± 1.2]. Small but detectable binding was identified in the substantia nigra/ventral tegmental area. Preliminary test-retest data in two subjects suggests BP-estimates to be reliable. Pre-treatment with haloperidol reduced BPs in regions showing specific binding with no detectable changes in cerebellum. Parallel imaging with [11C]-raclopride showed substantial differences in the globus pallidus. Conclusions [11C]-(+)-PHNO proved to be a D2/3-receptor agonist-radioligand with good brain uptake and favorable kinetics for PET in humans. [11C]-(+)-PHNO delineated D2/3-receptor rich brain regions with high signal-to-noise ratio. This is the first demonstration of a viable agonist-radioligand for D2 receptors in humans and opens the door for investigating D2high in health and disease. Background The high-affinity states of dopamine D2-receptors (D2high) are postulated to be functionally responsible for signal transduction. At present, no useful in vivo method exists to selectively measure D2high in humans, as current D2 radioligands for positron emission tomography (PET) are either not D2-selective or do not differentiate between D2 high- and low-affinity states. Methods The D2-agonist (+)-PHNO [(+)4-propyl-9-hydroxynaphthoxazine] was labeled with carbon-11 and studied with PET. Eight [11C]-(+)-PHNO scans were acquired in four healthy volunteers. Results We observed greatest [11C]-(+)-PHNO accumulation in caudate, putamen, and globus pallidus [binding potentials (BPs): 3.00 ± .4, 3.10 ± .2, and 4.17 ± 1.2]. Small but detectable binding was identified in the substantia nigra/ventral tegmental area. Preliminary test-retest data in two subjects suggests BP-estimates to be reliable. Pre-treatment with haloperidol reduced BPs in regions showing specific binding with no detectable changes in cerebellum. Parallel imaging with [11C]-raclopride showed substantial differences in the globus pallidus. Conclusions [11C]-(+)-PHNO proved to be a D2/3-receptor agonist-radioligand with good brain uptake and favorable kinetics for PET in humans. [11C]-(+)-PHNO delineated D2/3-receptor rich brain regions with high signal-to-noise ratio. This is the first demonstration of a viable agonist-radioligand for D2 receptors in humans and opens the door for investigating D2high in health and disease.