In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: Studies in non-human primates and transgenic mice (original) (raw)
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Biological Psychiatry, 2010
Background: Dopamine D 3 receptors are involved in the pathophysiology of several neuropsychiatric conditions. [ 11 C]-(ϩ)-PHNO is a radiolabeled D 2 and D 3 agonist, suitable for imaging the agonist binding sites (denoted D 2HIGH and D 3 ) of these receptors with positron emission tomography (PET). PET studies in nonhuman primates documented that, in vivo, [ 11 C]-(ϩ)-PHNO displays a relative selectivity for D 3 compared with D 2HIGH receptor sites and that the [ 11 C]-(ϩ)-PHNO signal is enriched in D 3 contribution compared with conventional ligands such as [ 11 C] raclopride.
Journal of Neurochemistry, 2006
11 C]-(+)-PHNO (4-propyl-9-hydroxynaphthoxazine) is a new agonist radioligand that provides a unique opportunity to measure the high-affinity states of the D 2 receptors (D 2 -high) using positron emission tomography (PET). Here we report on the distribution, displaceablity, specificity and modeling of [ 11 C]-(+)-PHNO and compare it with the well characterized antagonist D 2 radioligand, [ 11 C]raclopride, in cat. [ 11 C]-(+)-PHNO displayed high uptake in striatum with a mean striatal binding potential (BP) of 3.95 ± 0.85. Pre-treatment with specific D 1 (SCH23390), D 2 (raclopride, haloperidol) and D 3 receptor (SB-277011) antagonists indicated that [ 11 C]-(+)-PHNO binding in striatum is specific to D 2 receptors. Withinsubject comparisons showed that [ 11 C]-(+)-PHNO BP in striatum was almost 2.5-fold higher than that measured with [ 11 C]-(-)-NPA ([ 11 C]-(-)-N-propyl-norapomorphine). Compar-ison of the dose-effect of amphetamine (0.1, 0.5 and 2 mg/kg; i.v.) showed that [ 11 C]-(+)-PHNO was more sensitive to the dopamine releasing effect of amphetamine than [ 11 C]raclopride. Amphetamine induced up to 83 ± 4% inhibition of [ 11 C]-(+)-PHNO BP and only up to 56 ± 8% inhibition of [ 11 C]raclopride BP. Scatchard analyses of [ 11 C]-(+)-PHNO and [ 11 C]raclopride bindings in two cats showed that the B max 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 [ 11 C]-(+)-PHNO in brain, its high signal-to-noise ratio, its favorable in vivo kinetics and its high sensitivity to amphetamine shows that [ 11 C]-(+)-PHNO has highly suitable characteristics for probing the D 2 -high with PET.
Imaging dopamine receptors in humans with [ 11C]-(+)-PHNO: Dissection of D3 signal and anatomy
Neuroimage, 2011
Keywords: dopamine D3 receptors PET PHNO region of interest ROI ventral striatum VST ventral pallidum hypothalamus extended amygdala [ 11 C]-(+)-PHNO is a D3 preferring PET radioligand which has recently opened the possibility of imaging D3 receptors in the human brain in vivo. This imaging tool allows characterisation of the distribution of D3 receptors in vivo and further investigation of their functional role. The specific [ 11 C]-(+)-PHNO signal is a mixture of D3 and D2 components with the relative magnitude of each component determined by the regional receptor densities. An accurate and reproducible delineation of regions of interest (ROI) is therefore important for optimal analysis of human PET data. We present a set of anatomical guidelines for the delineation of D3 relevant ROIs including substantia nigra, hypothalamus, ventral pallidum/substantia innominata, ventral striatum, globus pallidus and thalamus. Delineation of these structures using this approach allowed for high intra-and inter-operator reproducibility. Subsequently we used a selective D3 antagonist to dissect the total [ 11 C]-(+)-PHNO signal in each region into its D3 and D2 components and estimated the regional fraction of the D3 signal (f PHNO D3 ). In descending order of magnitude the following results for the f PHNO D3 were obtained: hypothalamus = 100%, substantia nigra = 100%, ventral pallidum/ substantia innominata = 75%, globus pallidus = 65%, thalamus = 43%, ventral striatum = 26% and precommissural-ventral putamen = 6%. An automated approach for the delineation of these anatomical regions of interest was also developed and investigated in terms of its reproducibility and accuracy.
Blockade of 11C-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925
The International Journal of Neuropsychopharmacology, 2009
Dopamine D 3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [ 11 C](+)-PHNO is the first preferential D 3 receptor radioligand in humans, yet there are no blockade studies with a D 3 receptor antagonist in humans. This study characterized the blockade of [ 11 C](+)-PHNO binding by ABT-925, a D 3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean¡S.D.) was higher in substantia nigra (75¡10 %) and globus pallidus (64¡22 %) than in ventral striatum (44¡17 %), caudate (40¡18 %) and putamen (38¡17 %) (ANOVA : F 4,140 =15.02, p<0.001). The fractions of [ 11 C](+)-PHNO binding attributable to D 3 receptors in D 3 receptor-rich regions were 100 % (substantia nigra) and 90 % (globus pallidus), and in D 2 receptor-rich regions were 55 % (caudate) and 53 % (putamen). The ED 50 of ABT-925 was 4.37 mg/ml across regions. Our results demonstrate that [ 11 C](+)-PHNO binding can be blocked by a D 3 receptor antagonist and confirm preclinical findings that [ 11 C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D 3 receptors. Thus, [ 11 C](+)-PHNO seems a suitable PET radiotracer to estimate D 3 receptor occupancy in humans.
Synapse, 2012
Although [ 11 C]-(þ)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [ 11 C]-(þ)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [ 11 C]-(þ)-PHNO administered in a bolus þ infusion paradigm. Varying doses of unlabeled (þ)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 lg kg 21 ). The regional binding potential (BP ND ) and the corresponding doses of injected (þ)-PHNO were used as inputs in a model that quantified the affinity of (þ)-PHNO for the D2R and D3R, as well as the regional fractions of the [ 11 C]-(þ)-PHNO signal attributable to D3R binding. (þ)-PHNO in vivo affinity for the D3R (K d /f ND $ 0.23-0.56 nM) was 25-to 48-fold higher than that for the D2R (K d /f ND $ 11-14 nM). The tracer limits for (þ)-PHNO (dose associated with D3R occupancy $ 10%) were estimated at $0.02-0.04 lg kg 21 injected mass for anesthetized primate and at 0.01-0.02 lg kg 21 for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [ 11 C]-(þ)-PHNO. Synapse 66:489-500, 2012.
Synapse, 2004
We have evaluated the in vitro autoradiographic binding characteristics and in vivo brain distribution of two high-affinity dopamine D2/D3 receptor agonists, (Ϯ)-2-(N-phenethyl-N-1Ј-11 C-propyl)amino-5-hydroxytetralin ( 11 C-PPHT) and (Ϯ)-2-(Ncyclohexylethyl-N-1Ј-11 C-propyl)amino-5-hydroxytetralin ( 11 C-ZYY-339) in rodents and in monkeys using positron emission tomography (PET). In vitro autoradiograms in rat brain slices with 11 C-PPHT and 11 C-ZYY-339 revealed binding to dopaminergic regions in the striata, which was substantially (Ͼ90%) displaced by 10 M sulpiride. Striatal binding was also removed in the presence of 5-guanylylimidophosphate (Gpp(NH)p), indicative of binding of these radiotracers to the high-affinity (HA) state. The results of in vivo studies in rats exhibited binding of the two radiotracers to the striata (striata/ cerebellum approached 2 in 30 min). The regional selectivity to the striata was reduced by preadministration of haloperidol. PET studies in male rhesus monkeys using an ECAT EXACT HRϩ scanner indicated localization of 11 C-PPHT and 11 C-ZYY-339 in the striata and thalamus. Striata to cerebellum and thalamus to cerebellum ratios were low (1.5 and 1.3, respectively, at 30 min postinjection) for both 11 C-PPHT and 11 C-ZYY-339, apparently due to the slower nonspecific clearance from cerebellum. These findings with 11 C-PPHT and 11 C-ZYY-339 indicate the possibility of in vivo imaging of high-affinity state of dopamine D2/D3 receptors in both the striata and the thalamus. Synapse 54: 83-91, 2004.
Synapse, 2011
A series of microPET imaging studies were conducted in anesthetized rhesus monkeys using the dopamine D 3 -selective partial agonist, [ 18 F]5. There was variable uptake in regions of brain known to express a high density of D 3 receptors under baseline conditions. Pretreatment with lorazepam (1 mg/kg, i.v. 30 min) to reduce endogenous dopamine activity prior to tracer injection resulted in a dramatic increase in uptake in the caudate, putamen, and thalamus, and an increase in the binding potential (BP) values, a measure of D 3 receptor binding in vivo. These data indicate that there is a high level of competition between [ 18 F]5 and endogenous dopamine for D 3 receptors in vivo.
Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2007
The kinetic modeling of [11C]-(+)-PHNO binding to the dopamine D2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [11C]-(+)-PHNO is the first agonist radioligand for the D2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time-activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k3/k4 ratios. Coupling K1/k2 between brain regions (Method C) or fixing K1/k2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k3/k4 as compared with an unconstrained 2CM. The k3/k4 obtained with Method D ranged from 0.12+/-0.03 in cerebellum to 3.93+/-0.77 in GP and were similar ...