Positron emission tomography quantification of [11C]-(+)-PHNO binding in the human brain (original) (raw)
Related papers
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.
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.
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, 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.
Acta Neurologica Scandinavica, 1987
The regional kinetics of "C-N-methyl-spiperone ("C-NMSP) are described in the monkey brain under tracer conditions and after displacement and protection experiments. The primary aim of the study was to investigate different methodological problems associated with use of "C-NMSP in the quantitation of receptor properties before applying the method in clinical research. Special emphasis was placed on the evaluation of different maleh, Correia J A. Measurement of brain pH using ' T O , and positron emission tomography. . I Cerebral Blood Flow Metabolism 1984:4:8-16. University Hospital 29. Patlak C S, Blasberg R G , Fenstermacher J D. Grafical evaluation o f hlood t o hrain transfer constants from multiple time uptake data. J Cerehral Blood Flow Metabolism 1983:3: 1-7.
Molecular Imaging
We examined the reproducibility of using the constant infusion paradigm for equilibrium measurement of D2/3 receptors using [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) positron emission tomography (PET). Six subjects were scanned with a bolus plus constant infusion (Kbol = 80 minutes) of [11C]-(+)-PHNO. Binding potential (BPND) was computed using the equilibrium approach and compared to a simplified reference tissue model (SRTM). The rate of change in the concentration-activity curve from 60 to 90 minutes was -5 ± 13%/h in the caudate, putamen, substantia nigra, thalamus, and cerebellum but was 15 ± 15%/h in the ventral striatum and pallidum. Test-retest variability was lower in striatal compared to extrastriatal regions (4 ± 8% vs -8 ± 22%, respectively) using the equilibrium approach, with comparable results with SRTM. The equilibrium ratio and SRTM yielded reliable BPND estimates (intraclass correlation coefficient = 0.88 and 0.82, respectively). These studies support the re...
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.
Journal of Nuclear Medicine, 2009
It has been demonstrated in vitro that the dopamine D 2 receptor has 2 interconvertible affinity states for endogenous dopamine, referred to as the high-and the low-affinity states. 11 C-(R)-2-CH 3 O-N-n-propylnorapomorphine ( 11 C-MNPA) is a new agonist radioligand for in vivo imaging of the high-affinity state of dopamine D 2 receptors using PET. In the present study, the kinetics of 11 C-MNPA were examined for the first time, to our knowledge, in the human brain and analyzed using quantitative approaches with or without an arterial input function. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after an intravenous injection of 11 C-MNPA. The binding potential (BP ND ) was calculated using the indirect kinetic method, a kinetic compartment analysis with a metabolite-corrected arterial input function. BP ND was also calculated by the simplified reference tissue model (SRTM) and transient equilibrium methods, both with the cerebellum as the reference brain region. The results of the quantitative methods were compared in a cross-validation approach. Results: The highest regional radioactivity was observed in the putamen. BP ND values obtained by kinetic analysis were 0.82 6 0.09, 0.59 6 0.11, and 0.28 6 0.06, respectively, in the putamen, caudate, and thalamus. BP ND values obtained by the SRTM and transient equilibrium methods were in good agreement with those obtained by the indirect kinetic method (r 5 0.98 and r 5 0.93, respectively). For all quantification methods, the BP ND values based on data acquired from 0 to 60 min were in good agreement with those based on data acquired from 0 to 90 min (r 5 0.90-0.99). Conclusion: The regional distribution of 11 C-MNPA binding was in good agreement with previous PET studies of dopamine D 2 receptors in the human brain using antagonist radioligands. The results support routine use of the SRTM and transient equilibrium methods, that is, methods that do not require an arterial input function and need a scan time of only about 60 min. 11 C-MNPA should thus be useful for clinical research on the pathophysiology of neuropsychiatric disorders and estimation of dopamine D 2 receptor occupancy by dopaminergic drugs.