Preliminary assessment of extrastriatal dopamine d-2 receptor binding in the rodent and nonhuman primate brains using the high affinity radioligand, 18F-fallypride (original) (raw)
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Psychopharmacology, 2004
Rationale: [ 18 F]Fallypride is a new and promising radiotracer, suitable for imaging D 2 receptors with Positron Emission Tomography (PET) in both striatal and extrastriatal regions. The high signal to noise ratio of [ 18 F]fallypride has been attributed to its high affinity for D 2 receptors (K D of 0.03 nM, measured in vitro at room temperature). Objectives: We sought to further characterize this tracer in terms of its in vivo affinity, possible affinity differences between brain regions and dependence of in vitro affinity on temperature. Methods: PET scans were performed in baboons over a wide range of concentrations to measure the in vivo K D of [ 18 F]fallypride in striatal and extrastriatal regions. Several analytical approaches were used, including nonlinear kinetic modeling and equilibrium methods. Also, in vitro assays were performed at 22 and 37C. Results: No significant differences in the in vivo K D were detected between regions. In vivo K D of [ 18 F]fallypride was 0.22€0.05 nM in striatum, 0.17€0.05 nM in thalamus, and 0.21€0.07 nM in hippocampus. These values were intermediate between in vitro K D measured at 22 (0.04€0.03 nM) and 37 degrees (2.03€1.07 nM). Conclusion: The in vivo affinity of [ 18 F]fallypride was not as high as previously estimated from in vitro values. This property might contribute to the favorable kinetic properties of the tracer. The in vivo affinity was similar between striatal and extrastriatal regions. This result indicates that the measured regional in vivo affinities of this tracer are not affected by putative regional differences in endogenous dopamine, and that [ 18 F]fallypride is an appropriate tool to provide unbiased estimates of the occupancy of D 2 receptors by antipsychotic drugs in striatal and extrastriatal regions.
Quantification of D2Like Dopamine Receptors in the Human Brain with 18F-Desmethoxyfallypride
2000
Substituted benzamides such as 11 C-raclopride or 123 I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D 2 -like dopamine (DA) receptors. 18 F-Desmethoxyfallypride ( 18 F-DMFP) is a benzamide tracer with the advantage of an 18 F label. We optimized the synthesis and evaluated 18 F-DMFP in PET studies on healthy human volunteers. Methods: The affinity of DMFP for D 2 -like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand 3 H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 Ϯ 54 MBq (mean Ϯ SD) 18 F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods). Results: The mean inhibition constant (K i ) of DMFP was 15 Ϯ 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods. Conclusion: Our study demonstrates that 18 F-DMFP is a highly reliable tracer for PET imaging of D 2 -like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the 18 F label and the favorable imaging properties, 18 F-DMFP could become an efficient substitute for 11 C-raclopride in a clinical context.
Brain Research, 2005
The ability to measure amphetamine-induced dopamine release in extrastriatal brain regions in the non-human primates was evaluated by using the dopamine D-2/D-3 receptor radioligand, 18 F-fallypride. These regions included the thalamus, amygdala, pituitary, temporal cortex and frontal cortex as well as putamen, caudate and ventral striatum. The positron emission tomography (PET) studies involved control studies, which extended to 3 h, and the amphetamine-challenge studies, which involved administration of d-amphetamine (approx. 0.5-1 mg/ kg, i.v.). PET data analysis employed the distribution volume ratio method (DVR) in which the cerebellum was used as a reference region. Our results show a substantial decrease in the binding potential of 18 F-fallypride in extrastriatal regions: thalamus (À20%), amygdala (À39%) and pituitary (À14%). Putamen, caudate and ventral striatum also exhibited significant decreases (À20%). The decrease in 18 F-fallypride binding in the extrastriatal regions points to the importance of dopaminergic neurotransmission in these brain regions. Furthermore, our findings support the use of 18 F-fallypride to measure extrastriatal dopamine release. D
Synapse, 2011
In this study we compared two different D2/3 receptor ligands, [ 18 F]fallypride and [ 18 F]desmethoxyfallypride ([ 18 F]DMFP) with respect to duration of the scan, visualization of extrastriatal receptors and binding potentials in the rat brain. In addition we studied the feasibility of using these tracers following a period of awake tracer uptake, during which the animal may perform a behavioral task. Male Sprague Dawley rats were imaged with [ 18 F]fallypride and with [ 18 F]DMFP in four different studies using microPET. All scans were performed under isoflurane anesthesia. The first (test) and second (retest) study were 150 min baseline scans. No retest scans were performed with [ 18 F]DMFP. A third study was a 60 minutes awake uptake of radiotracer followed by a 90 minutes scan. A fourth study was a 150 min competition scan with haloperidol (0.2 mg/Kg) administered via tail vein at 90 min post [ 18 F]fallypride injection and 60 min post [ 18 F]DMFP. For the test-retest studies, binding potential (BP ND ) was measured using both Logan non-invasive (LNI) method and the interval ratios (ITR) method. Cerebellum was used as a reference region. For the third study the binding was measured only with the ITR method and the results were compared to the baseline results. Studies showed that the average transient equilibrium time in the dorsal striatum was at 90 min for [ 18 F]fallypride and 30 min for [ 18 F]DMFP. The average binding potentials (BP ND ) for [ 18 F]fallypride were 14.4 in dorsal striatum (DSTR), 6.8 in ventral striatum (VSTR), 1.3 in substantia nigra/ventral tegmental area (SN/VTA), 1.4 in colliculi (COL), and 1.5 in central grey area (CG). In the case of [ 18 F]DMFP the average BP ND values were 2.2 in DSTR, 2.7 in VSTR, and 0.8 in SN/VTA. The haloperidol blockade showed detectable decrease in binding of both tracers in striatal regions with a faster displacement of [ 18 F]DMFP. No significant changes in BP ND of [ 18 F]fallypride due to the initial awake state of the animal was found whereas BP ND of [ 18 F]DMFP was significantly higher in the awake state compared to baseline. We were able to demonstrate that dynamic PET using MicroPET Inveon allows quantification of both striatal and extrastriatal [ 18 F]fallypride binding in rats in vivo. Quantification of the striatal regions could be achieved with [ 18 F]DMFP.
Synapse, 2000
18 F]Fallypride is a highly selective, high-affinity dopamine D-2 receptor ligand. The high affinity, K D ϭ 30 pM, makes it a suitable candidate for visualizing both striatal and extrastriatal binding in the brain. In this work, dynamic PET studies of two macaque monkeys were acquired along with arterial plasma samples. Compartmental analysis and Logan plots were used to analyze the striatum, thalamus, frontal, and temporal cortices and to validate a reference region of analysis which yields a distribution volume ratio (DVR). The cerebellum was used as the reference region. The results indicate that all methods of analysis are in close agreement over all the analyzed regions in the brain. The average DVRs for the two monkeys was found to be: caudate ϭ 26, putamen ϭ 29, thalamus ϭ 3.8, frontal ctx ϭ 1.7, and temporal ctx ϭ 1.7 on a high-resolution PET scanner. It was found that a scan time of 2 h is needed to accurately estimate the DVR for all regions of the brain. The striatal regions require the longest to linearize and are the most sensitive to variations in the average tissue-to-plasma efflux constant, k 2 . For the extrastriatal regions, the effect of the k 2 term on DVR calculation is negligible. Repeatability measurements for all regions were found to be within 10% using the DVR parameter. Synapse 38:71-79, 2000.
NeuroImage, 2004
Dopaminergic neurotransmission in extrastriatal regions may play a crucial role in the pathophysiology and treatment of neuropsychiatric disorders. The high-affinity radioligands [ 11 C]FLB 457, [ 123 I]epidepride, and [ 18 F]fallypride are now used in clinical studies to measure these low-density receptor populations in vivo. However, a single determination of the regional binding potential (BP) does not differentiate receptor density (B max ) from the apparent affinity (K D ). In this positron emission tomography (PET) study, we measured extrastriatal dopamine D2 receptor density (B max ) and apparent affinity (K D ) in 10 healthy subjects using an in vivo saturation approach. Each subject participated in two to three PET measurements with different specific radioactivity of [ 11 C]FLB 457. The commonly used simplified reference tissue model (SRTM) was used in a comparison of BP values with the B max values obtained from the saturation analysis. The calculated regional receptor density values were of the same magnitude (0.33 -1.68 nM) and showed the same rank order as reported from postmortem studies, that is, in descending order thalamus, lateral temporal cortex, anterior cinguli, and frontal cortex. The affinity ranged from 0.27 to 0.43 nM, that is, approximately 10 -20 times the value found in vitro (20 pM). The area under the cerebellar time activity curve (TAC) was slightly lower (11 F 8%, mean F SD, P = 0.004, n = 10) after injection of low as compared with high specific radioactivity, indicating sensitivity to the minute density of dopamine D2 receptors in the this region. The results of the present study support that dopamine D2 receptor density and affinity can be differentiated in low-density regions using a saturation approach. There was a significant ( P < 0.001) correlation between the binding potential calculated with SRTM and the receptor density (B max ), which supports the use of BP in clinical studies where differentiation of B max and K D is not required. In such studies, the mass of FLB 457 has to be less than 0.5 Mg injected to avoid a mass effect of the radioligand itself. D 2004 Elsevier Inc. All rights reserved.
Background: Values of binding potentials (BPND) of dopamine D2/3 receptors differ in different regions of the brain, but we do not know with certainty how much of this difference is due either to different receptor numbers, or to different affinities of tracers to the receptors, or to both. Method: We tested the claim that both striatal and extrastriatal dopamine D2/3 receptor availabilities vary with age in vivo in humans by determining the values of BPND of the specific radioligand [11C]raclopride. We determined values of BPND in striatal and extrastriatal volumes-of-interest (VOI) with the same specific receptor radioligand. Results: We estimated values of BPND in individual voxels of brains of healthy volunteers in vivo, and we obtained regional averages of VOI by dynamic positron emission tomography (PET). We calculated average values of BPND in caudate nucleus and putamen of striatum, and in frontal, occipital, parietal, and temporal cortices of the forebrain, by means of four...
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.
Journal of Cerebral Blood Flow and Metabolism, 2010
18 F-Fallypride and 11 C-FLB457 are commonly used PET radioligands for imaging extrastriatal dopamine D 2 /D 3 receptors, but differences in their in vivo kinetics may affect the sensitivity for measuring subtle changes in receptor binding. Focusing on regions of low binding, a direct comparison of the kinetics of 18 F-fallypride and 11 C-FLB457 was made using a MI protocol. Injection protocols were designed to estimate K 1 , k 2 , f ND k on , B max , and k off in the midbrain and cortical regions of the rhesus monkey. 11 C-FLB457 cleared from the arterial plasma faster and yielded a ND space distribution volume (K 1 /k 2 ) that is three times higher than 18 F-fallypride, primarily due to a slower k 2 (FAL:FLB; k 2 = 0.54 min À1 :0.18 min À1 ). The dissociation rate constant, k off , was slower for 11 C-FLB457, resulting in a lower K Dapp than 18 F-fallypride (FAL:FLB; 0.39 nM:0.13 nM). Specific D 2 /D 3 binding could be detected in the cerebellum for 11 C-FLB457 but not 18 F-fallypride. Both radioligands can be used to image extrastriatal D 2 /D 3 receptors, with 11 C-FLB457 providing greater sensitivity to subtle changes in low-receptor-density cortical regions and 18 F-fallypride being more sensitive to endogenous dopamine displacement in medium-to-high-receptor-density regions. In the presence of specific D 2 /D 3 binding in the cerebellum, reference region analysis methods will give a greater bias in BP ND with 11 C-FLB457 than with 18 F-fallypride.