Imaging Dopamine D3 Receptors in the Human Brain with Positron Emission Tomography, [11C]PHNO, and a Selective D3 Receptor Antagonist (original) (raw)
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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, 2009
Examination of dopamine-D3 (D3) receptors with positron emission tomography (PET) have been hampered in the past by the lack of a PET ligand with sufficient selectivity for D3 over dopamine-D2 (D2) receptors. The two types co-localize in the brain, with D2 density significantly higher than D3, hence nonselective PET ligands inform on D2, rather than D3 status. [ 11 C]-(1)-PHNO is a novel PET ligand with a preferential affinity for D3 over D2. We used the selective D3 antagonist, SB-277011 to dissect regional fractions of the [ 11 C]-(1)-PHNO signal attributable to D3 and D2 in primate brain. The results were compared with quantitative autoradiography with 3 H-(1)-PHNO in wild-type, D2-knockout , and D3-knockout mice examined at baseline and following administration of SB-277011. Both sets of results converged to indicate a predominant D3-related component to (1)-PHNO binding in extra-striatal regions, with binding in the midbrain being entirely attributable to D3. The midbrain is thus an excellent target region to examine D3 receptor occupancy with [ 11 C]-(1)-PHNO PET in vivo.
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.
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.
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.
Psychopharmacology, 2019
Rationale F17464, a dopamine D3 receptor antagonist with relatively high D3 selectivity (70 fold vs D2 in vitro), exhibits an antipsychotic profile in preclinical studies, and therapeutic efficacy was demonstrated in a randomized placebo-controlled clinical trial in patients with schizophrenia (Bitter et al. Neuropsychopharmacology 44(11):1917-1924, 2019). Objective This open-label study in healthy male subjects aimed at characterizing F17464 binding to D3/D2 receptors and the time course of receptor occupancy using positron emission tomography (PET) imaging with a D3-preferring tracer, [ 11 C]-(+)-PHNO. Methods PET scans were performed at baseline and following a single 30 mg or 15 mg dose of F17464 (3 subjects/dose), and blood samples were collected for pharmacokinetic analysis. Receptor occupancy was calculated based upon reduction in binding potential of the tracer following F17464 administration. The relationship between plasma F17464 concentration and D3/D2 receptor occupancy was modeled and the plasma concentration corresponding to 50% receptor occupancy (EC 50) calculated. Results Both doses of F17464 robustly blocked [ 11 C]-(+)-PHNO D3 receptor binding, with substantial occupancy from 1 h postadministration, which increased at 6-9 h (89-98% and 79-87% for the 30 mg and 15 mg groups, respectively) and remained detectable at 22 h. In contrast, D2 binding was only modestly blocked at all time points (< 18%). F17464 exhibited a combination of rapid peripheral kinetics and hysteresis (persistence of binding 22 h post-dose despite low plasma concentration). The best estimate of the EC 50 was 19 ng ml −1 (~40 nM). Conclusion Overall, F17464 was strongly D3-selective in healthy volunteers, a unique profile for an antipsychotic candidate drug.
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 ...