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Jean Logan - One of the best experts on this subject based on the ideXlab platform.
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Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-Raclopride for small animal imaging.
Journal of neuroscience methods, 2004Co-Authors: Wynne K. Schiffer, David Alexoff, Jean Logan, Colleen Shea, Stephen L. DeweyAbstract:In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-Raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of Raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-Raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 μg), with an ED50 of 8.55 ± 5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of Raclopride below 2.0 pmol/ml (0.326 μg). Increases in ECF DA were produced by mass doses of Raclopride over 3.9 pmol/ml (0.329 μg) with an ED50 of 8.53 ± 2.48 pmol/ml. Taken together, it appears that an optimal range of Raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound.
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Imaging dopamine receptors in the rat striatum with the MicroPET R4: kinetic analysis of [11C]Raclopride binding using graphical methods.
Methods in enzymology, 2004Co-Authors: David Alexoff, P Vaska, Jean LoganAbstract:Publisher Summary This chapter describes the binding potential computed for 15 [ 11 C]Raclopride studies in the rat striatum using the micro-PET R4. In two of these studies, a 1-mg/kg blocking dose of Raclopride was coadministered with the tracer to measure nonspecific binding of the tracer. The remaining studies were carried out with varying doses of [ 11 C]Raclopride of varying specific activity. Data are summarized as the binding potential as a function of Raclopride mass injected. The curve is the best fit to a single-site ligand receptor model allowing for fitting of the modified equilibrium constants. Image data were corrected for spillover from the intraorbital lachrymal glands but were not corrected for partial volume averaging. The microPET R4, with a FWHM resolution is expected to give a truer measure of striatal [ 11 C]Raclopride concentration, and therefore, gives a larger binding potential. Determinations of binding potential using the graphical method were compared with the values obtained using a compartmental model without blood sampling. The results support the use of the noninvasive graphical analysis methodology with [ 11 C]Raclopride, and the microPET R4 to measure dopamine receptor availability in the rat striatum.
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reproducibility of 11c Raclopride binding in the rat brain measured with the micropet r4 effects of scatter correction and tracer specific activity
The Journal of Nuclear Medicine, 2003Co-Authors: David Alexoff, P Vaska, Douglas A Marsteller, Timofei Gerasimov, Jean Logan, Joanna S Fowler, Nicholas B Taintor, Panayotis K Thanos, Nora D VolkowAbstract:A new generation of commercial animal PET cameras may accelerate drug development by streamlining preclinical testing in laboratory animals. However, little information on the feasibility of using these machines for quantitative PET in small animals is available. Here we investigate the reproducibility of microPET imaging of 11C-Raclopride in the rat brain and the effects of tracer-specific activity and photon scatter correction on measures of D2 receptor (D2R) availability. Methods: Sprague-Dawley rats (422 ± 29 g; n = 7) were anesthetized with ketamine/xylazine and catheterized for tail vein injection of 11C-Raclopride. Each animal was positioned prone in the microPET, centering the head in the field of view. MicroPET data was collected for 60 min—starting at 11C-Raclopride injection—and binned into 24 time frames (6 × 10 s, 3 × 20 s, 8 × 60 s, 4 × 200 s, 3 × 600 s). In 3 studies, 11C-Raclopride was administered a second time in the same animal, with 2–4 h between injections. In a fourth animal, Raclopride (1 mg/kg) was coinjected with 11C-Raclopride for the second injection. Three rats received a single dose of 11C-Raclopride. The range of doses for all studies was 6.11–18.54 MBq (165–501 μCi). The specific activity at injection was 4.07–48.1 GBq/μmol (0.11–1.3 Ci/μmol). Region-of-interest analysis was performed and the distribution volume ratio (DVR) was computed for striatum/cerebellum using sinograms uncorrected and corrected for scatter using a tail-fit method. Results: Test-retest results showed that the 11C-Raclopride microPET DVR was reproducible (change in DVR = −8.3% ± 4.4%). The average DVR from 6 rats injected with high specific activity ( 1.5 nmol/kg. Scatter fractions within the rat head were ∼25%–45% resulting in an average increase of DVR of 3.5% (range, 0%–10%) after correction. Conclusion: This study shows that the 11C-Raclopride microPET-derived DVR is reproducible and suitable for studying D2R availability in the rat brain. MicroPET sensitivity was sufficient to determine reproducible DVRs from 11C-Raclopride injections of 9.25 MBq (∼250 μCi). However, the effect of tracer mass on the DVR should be considered for studies using more than ∼1–2 nmol/kg Raclopride, and scatter correction has a measurable impact on the results.
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Reproducibility of 11C-Raclopride Binding in the Rat Brain Measured with the MicroPET R4: Effects of Scatter Correction and Tracer Specific Activity
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2003Co-Authors: David Alexoff, P Vaska, Douglas A Marsteller, Timofei Gerasimov, Jean Logan, Joanna S Fowler, Nicholas B Taintor, Panayotis K Thanos, Nora D VolkowAbstract:UNLABELLED A new generation of commercial animal PET cameras may accelerate drug development by streamlining preclinical testing in laboratory animals. However, little information on the feasibility of using these machines for quantitative PET in small animals is available. Here we investigate the reproducibility of microPET imaging of (11)C-Raclopride in the rat brain and the effects of tracer-specific activity and photon scatter correction on measures of D2 receptor (D2R) availability. METHODS Sprague-Dawley rats (422 +/- 29 g; n = 7) were anesthetized with ketamine/xylazine and catheterized for tail vein injection of (11)C-Raclopride. Each animal was positioned prone in the microPET, centering the head in the field of view. MicroPET data was collected for 60 min-starting at (11)C-Raclopride injection-and binned into 24 time frames (6 x 10 s, 3 x 20 s, 8 x 60 s, 4 x 200 s, 3 x 600 s). In 3 studies, (11)C-Raclopride was administered a second time in the same animal, with 2-4 h between injections. In a fourth animal, Raclopride (1 mg/kg) was coinjected with (11)C-Raclopride for the second injection. Three rats received a single dose of (11)C-Raclopride. The range of doses for all studies was 6.11-18.54 MBq (165-501 micro Ci). The specific activity at injection was 4.07-48.1 GBq/ micro mol (0.11-1.3 Ci/ micro mol). Region-of-interest analysis was performed and the distribution volume ratio (DVR) was computed for striatum/cerebellum using sinograms uncorrected and corrected for scatter using a tail-fit method. RESULTS Test-retest results showed that the (11)C-Raclopride microPET DVR was reproducible (change in DVR = -8.3% +/- 4.4%). The average DVR from 6 rats injected with high specific activity ( 1.5 nmol/kg. Scatter fractions within the rat head were approximately 25%-45% resulting in an average increase of DVR of 3.5% (range, 0%-10%) after correction. CONCLUSION This study shows that the (11)C-Raclopride microPET-derived DVR is reproducible and suitable for studying D2R availability in the rat brain. MicroPET sensitivity was sufficient to determine reproducible DVRs from (11)C-Raclopride injections of 9.25 MBq (approximately 250 micro Ci). However, the effect of tracer mass on the DVR should be considered for studies using more than approximately 1-2 nmol/kg Raclopride, and scatter correction has a measurable impact on the results.
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PET Studies of the Effect of the Antidepressant Drugs Nefazodone or Paroxetine on [11C]Raclopride Binding in Human Brain.
Clinical positron imaging : official journal of the Institute for Clinical P.E.T, 1999Co-Authors: Joanna S Fowler, Jean Logan, Nora D Volkow, Gene-jack Wang, John Ieni, Naomi Pappas, Stephen L. DeweyAbstract:Serotonin modulates dopamine release in the striatum. In this study we set out to determine whether nefazodone and paroxetine, two antidepressant drugs that interact with the brain serotonin system, produce detectable changes in synaptic dopamine in vivo in the human brain using positron emission tomography (PET) and [11C]Raclopride, a dopamine D-2 receptor specific radiotracer that is sensitive to changes in synaptic dopamine. Three normal healthy human volunteers had 4 PET/[11C]Raclopride scans each in 2 sessions. In the first session, subjects had a baseline [11C]Raclopride scan and a second scan 1 hour following the oral administration of either nefazodone (200 mg PO) or paroxetine (20 mg PO). Four to 6 weeks later, in a second PET/[11C]Raclopride session, the same subjects received the other drug for comparison. Neither nefazodone nor paroxetine produced significant changes in [11C]Raclopride binding. This and other reports in the literature indicate that different drugs that affect the serotonin system do not produce consistent and predictable changes in [11C]Raclopride binding and that a full understanding of their actions on serotonin and the associated changes in dopamine requires further investigation.
David Alexoff - One of the best experts on this subject based on the ideXlab platform.
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Imaging dopamine release with Positron Emission Tomography (PET) and 11C-Raclopride in freely moving animals
NeuroImage, 2008Co-Authors: Vinal Patel, David Alexoff, Dianne E. Lee, Stephen L. Dewey, Wynne K. SchifferAbstract:Abstract We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11 C-Raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11 C-Raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled Raclopride, pretreatment with methamphetamine (METH) or pretreatment with γ-vinyl-GABA [S(+)-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11 C-Raclopride binding was compared to data from animals that were anesthetized for the uptake period (“Anesthetized Uptake”) and full time activity curves were used to calculate 11 C-Raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11 C-Raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold Raclopride, both groups demonstrated a ~ 30% reduction in 11 C-Raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11 C-Raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.
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Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-Raclopride for small animal imaging.
Journal of neuroscience methods, 2004Co-Authors: Wynne K. Schiffer, David Alexoff, Jean Logan, Colleen Shea, Stephen L. DeweyAbstract:In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-Raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of Raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-Raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 μg), with an ED50 of 8.55 ± 5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of Raclopride below 2.0 pmol/ml (0.326 μg). Increases in ECF DA were produced by mass doses of Raclopride over 3.9 pmol/ml (0.329 μg) with an ED50 of 8.53 ± 2.48 pmol/ml. Taken together, it appears that an optimal range of Raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound.
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Imaging dopamine receptors in the rat striatum with the MicroPET R4: kinetic analysis of [11C]Raclopride binding using graphical methods.
Methods in enzymology, 2004Co-Authors: David Alexoff, P Vaska, Jean LoganAbstract:Publisher Summary This chapter describes the binding potential computed for 15 [ 11 C]Raclopride studies in the rat striatum using the micro-PET R4. In two of these studies, a 1-mg/kg blocking dose of Raclopride was coadministered with the tracer to measure nonspecific binding of the tracer. The remaining studies were carried out with varying doses of [ 11 C]Raclopride of varying specific activity. Data are summarized as the binding potential as a function of Raclopride mass injected. The curve is the best fit to a single-site ligand receptor model allowing for fitting of the modified equilibrium constants. Image data were corrected for spillover from the intraorbital lachrymal glands but were not corrected for partial volume averaging. The microPET R4, with a FWHM resolution is expected to give a truer measure of striatal [ 11 C]Raclopride concentration, and therefore, gives a larger binding potential. Determinations of binding potential using the graphical method were compared with the values obtained using a compartmental model without blood sampling. The results support the use of the noninvasive graphical analysis methodology with [ 11 C]Raclopride, and the microPET R4 to measure dopamine receptor availability in the rat striatum.
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reproducibility of 11c Raclopride binding in the rat brain measured with the micropet r4 effects of scatter correction and tracer specific activity
The Journal of Nuclear Medicine, 2003Co-Authors: David Alexoff, P Vaska, Douglas A Marsteller, Timofei Gerasimov, Jean Logan, Joanna S Fowler, Nicholas B Taintor, Panayotis K Thanos, Nora D VolkowAbstract:A new generation of commercial animal PET cameras may accelerate drug development by streamlining preclinical testing in laboratory animals. However, little information on the feasibility of using these machines for quantitative PET in small animals is available. Here we investigate the reproducibility of microPET imaging of 11C-Raclopride in the rat brain and the effects of tracer-specific activity and photon scatter correction on measures of D2 receptor (D2R) availability. Methods: Sprague-Dawley rats (422 ± 29 g; n = 7) were anesthetized with ketamine/xylazine and catheterized for tail vein injection of 11C-Raclopride. Each animal was positioned prone in the microPET, centering the head in the field of view. MicroPET data was collected for 60 min—starting at 11C-Raclopride injection—and binned into 24 time frames (6 × 10 s, 3 × 20 s, 8 × 60 s, 4 × 200 s, 3 × 600 s). In 3 studies, 11C-Raclopride was administered a second time in the same animal, with 2–4 h between injections. In a fourth animal, Raclopride (1 mg/kg) was coinjected with 11C-Raclopride for the second injection. Three rats received a single dose of 11C-Raclopride. The range of doses for all studies was 6.11–18.54 MBq (165–501 μCi). The specific activity at injection was 4.07–48.1 GBq/μmol (0.11–1.3 Ci/μmol). Region-of-interest analysis was performed and the distribution volume ratio (DVR) was computed for striatum/cerebellum using sinograms uncorrected and corrected for scatter using a tail-fit method. Results: Test-retest results showed that the 11C-Raclopride microPET DVR was reproducible (change in DVR = −8.3% ± 4.4%). The average DVR from 6 rats injected with high specific activity ( 1.5 nmol/kg. Scatter fractions within the rat head were ∼25%–45% resulting in an average increase of DVR of 3.5% (range, 0%–10%) after correction. Conclusion: This study shows that the 11C-Raclopride microPET-derived DVR is reproducible and suitable for studying D2R availability in the rat brain. MicroPET sensitivity was sufficient to determine reproducible DVRs from 11C-Raclopride injections of 9.25 MBq (∼250 μCi). However, the effect of tracer mass on the DVR should be considered for studies using more than ∼1–2 nmol/kg Raclopride, and scatter correction has a measurable impact on the results.
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Reproducibility of 11C-Raclopride Binding in the Rat Brain Measured with the MicroPET R4: Effects of Scatter Correction and Tracer Specific Activity
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2003Co-Authors: David Alexoff, P Vaska, Douglas A Marsteller, Timofei Gerasimov, Jean Logan, Joanna S Fowler, Nicholas B Taintor, Panayotis K Thanos, Nora D VolkowAbstract:UNLABELLED A new generation of commercial animal PET cameras may accelerate drug development by streamlining preclinical testing in laboratory animals. However, little information on the feasibility of using these machines for quantitative PET in small animals is available. Here we investigate the reproducibility of microPET imaging of (11)C-Raclopride in the rat brain and the effects of tracer-specific activity and photon scatter correction on measures of D2 receptor (D2R) availability. METHODS Sprague-Dawley rats (422 +/- 29 g; n = 7) were anesthetized with ketamine/xylazine and catheterized for tail vein injection of (11)C-Raclopride. Each animal was positioned prone in the microPET, centering the head in the field of view. MicroPET data was collected for 60 min-starting at (11)C-Raclopride injection-and binned into 24 time frames (6 x 10 s, 3 x 20 s, 8 x 60 s, 4 x 200 s, 3 x 600 s). In 3 studies, (11)C-Raclopride was administered a second time in the same animal, with 2-4 h between injections. In a fourth animal, Raclopride (1 mg/kg) was coinjected with (11)C-Raclopride for the second injection. Three rats received a single dose of (11)C-Raclopride. The range of doses for all studies was 6.11-18.54 MBq (165-501 micro Ci). The specific activity at injection was 4.07-48.1 GBq/ micro mol (0.11-1.3 Ci/ micro mol). Region-of-interest analysis was performed and the distribution volume ratio (DVR) was computed for striatum/cerebellum using sinograms uncorrected and corrected for scatter using a tail-fit method. RESULTS Test-retest results showed that the (11)C-Raclopride microPET DVR was reproducible (change in DVR = -8.3% +/- 4.4%). The average DVR from 6 rats injected with high specific activity ( 1.5 nmol/kg. Scatter fractions within the rat head were approximately 25%-45% resulting in an average increase of DVR of 3.5% (range, 0%-10%) after correction. CONCLUSION This study shows that the (11)C-Raclopride microPET-derived DVR is reproducible and suitable for studying D2R availability in the rat brain. MicroPET sensitivity was sufficient to determine reproducible DVRs from (11)C-Raclopride injections of 9.25 MBq (approximately 250 micro Ci). However, the effect of tracer mass on the DVR should be considered for studies using more than approximately 1-2 nmol/kg Raclopride, and scatter correction has a measurable impact on the results.
Stephen L. Dewey - One of the best experts on this subject based on the ideXlab platform.
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Imaging dopamine release with Positron Emission Tomography (PET) and 11C-Raclopride in freely moving animals
NeuroImage, 2008Co-Authors: Vinal Patel, David Alexoff, Dianne E. Lee, Stephen L. Dewey, Wynne K. SchifferAbstract:Abstract We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11 C-Raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11 C-Raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled Raclopride, pretreatment with methamphetamine (METH) or pretreatment with γ-vinyl-GABA [S(+)-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11 C-Raclopride binding was compared to data from animals that were anesthetized for the uptake period (“Anesthetized Uptake”) and full time activity curves were used to calculate 11 C-Raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11 C-Raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold Raclopride, both groups demonstrated a ~ 30% reduction in 11 C-Raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11 C-Raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.
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Development of a simultaneous PET/microdialysis method to identify the optimal dose of 11C-Raclopride for small animal imaging.
Journal of neuroscience methods, 2004Co-Authors: Wynne K. Schiffer, David Alexoff, Jean Logan, Colleen Shea, Stephen L. DeweyAbstract:In the field of small animal positron emission tomography (PET), the assumptions underlying human and primate kinetic models may not be sustained in rodents. That is, the threshold dose at which a pharmacologic response occurs may be lower in small animals. In order to define this relationship, we combined microPET imaging using 11C-Raclopride with microdialysis measures of extracellular fluid (ECF) dopamine (DA). In addition, we performed a series of studies in which a known mass of Raclopride was microinfused into one striatum prior to a high specific activity (SA) systemic injection of 11C-Raclopride. This single-injection approach provided a high and low SA region of radiotracer binding in the same animal during the same scanning session. Our data demonstrate that the binding potential (BP) declines above 3.5 pmol/ml (0.35 μg), with an ED50 of 8.55 ± 5.62 pmol/ml. These data also provide evidence that BP may be compromised by masses of Raclopride below 2.0 pmol/ml (0.326 μg). Increases in ECF DA were produced by mass doses of Raclopride over 3.9 pmol/ml (0.329 μg) with an ED50 of 8.53 ± 2.48 pmol/ml. Taken together, it appears that an optimal range of Raclopride mass exists between 2.0 and 3.5 pmol/ml, around which the measured BP can be compromised by system sensitivity, endogenous DA, or excessive competition with unlabeled compound.
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PET Studies of the Effect of the Antidepressant Drugs Nefazodone or Paroxetine on [11C]Raclopride Binding in Human Brain.
Clinical positron imaging : official journal of the Institute for Clinical P.E.T, 1999Co-Authors: Joanna S Fowler, Jean Logan, Nora D Volkow, Gene-jack Wang, John Ieni, Naomi Pappas, Stephen L. DeweyAbstract:Serotonin modulates dopamine release in the striatum. In this study we set out to determine whether nefazodone and paroxetine, two antidepressant drugs that interact with the brain serotonin system, produce detectable changes in synaptic dopamine in vivo in the human brain using positron emission tomography (PET) and [11C]Raclopride, a dopamine D-2 receptor specific radiotracer that is sensitive to changes in synaptic dopamine. Three normal healthy human volunteers had 4 PET/[11C]Raclopride scans each in 2 sessions. In the first session, subjects had a baseline [11C]Raclopride scan and a second scan 1 hour following the oral administration of either nefazodone (200 mg PO) or paroxetine (20 mg PO). Four to 6 weeks later, in a second PET/[11C]Raclopride session, the same subjects received the other drug for comparison. Neither nefazodone nor paroxetine produced significant changes in [11C]Raclopride binding. This and other reports in the literature indicate that different drugs that affect the serotonin system do not produce consistent and predictable changes in [11C]Raclopride binding and that a full understanding of their actions on serotonin and the associated changes in dopamine requires further investigation.
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Serotonergic modulation of dopamine measured with [11C]Raclopride and PET in normal human subjects
The American journal of psychiatry, 1997Co-Authors: Gwenn S. Smith, David Alexoff, Jean Logan, Stephen L. Dewey, Jonathan D. Brodie, Stephen A. Vitkun, Philip Simkowitz, Ralf Schloesser, Arlene Hurley, Thomas B. CooperAbstract:Objective: This study was undertaken to measure serotonergic modulation of dopamine in vivo by using positron emission tomography (PET), a radiotracer for the striatal dopamine D2 receptor ([11C]Raclopride), and a pharmacologic challenge of the serotonin system (d,l-fenfluramine). Method: Two PET studies using [11C]Raclopride were performed in 11 normal male subjects before administration of the serotonin-releasing agent and reuptake inhibitor fenfluramine (60 mg p.o.) and 3 hours afterward. A graphical analysis method was used with the [11C]Raclopride data to derive the distribution volume of D2 receptors. Plasma levels of fenfluramine, norfenfluramine, homovanillic acid (HVA), cortisol, and prolactin were determined. Results: Levels of fenfluramine and prolactin were elevated 2 hours after fenfluramine administration and remained significantly elevated during the second scan, while levels of HVA and cortisol were not altered significantly during the time of scanning. A significant decrease in the specific binding (striatum) and the nonspecific binding subtracted from the specific binding (striatum minus cerebellum) of [11C]Raclopride was observed. The rate of metabolism of [11C]Raclopride and the nonspecific binding (cerebellum) were not significantly altered by the fenfluramine intervention. Conclusions: The observed decrease in [11C]Raclopride binding is consistent with an increase in dopamine concentrations and with the ability of serotonin to stimulate dopamine activity. The ability to measure serotonergic modulation of dopamine in vivo may have implications for the study of etiologic and therapeutic mechanisms in schizophrenia, major depressive disorder, obsessive-compulsive disorder, and substance abuse. (Am J Psychiatry 1997; 154:490‐496)
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reproducibility of repeated measures of carbon 11 Raclopride binding in the human brain
The Journal of Nuclear Medicine, 1993Co-Authors: Nora D Volkow, David Alexoff, Jean Logan, Joanna S Fowler, Stephen L. Dewey, Gene-jack Wang, David J Schlyer, Robert R Macgregor, Colleen Shea, Robert HitzemannAbstract:: Carbon-11-Raclopride has been successfully utilized with PET to assess changes in endogenous dopamine concentration after pharmacological intervention in the living baboon brain. For similar studies to be done in humans, measurements of 11C-Raclopride with no intervention need to be reproducible. In order to test the reproducibility (test-retest) of 11C-Raclopride binding in the human brain, we performed repeated studies on two different days. Studies were done in five normal controls with no pharmacological intervention. Time-activity (%dose/cc) curves for 11C-Raclopride in the basal ganglia (BG) and cerebellum (CBL) were highly reproducible with an average difference in peak uptake for repeated studies in the same individual of 4%. The BG to CBL ratio for the average activity concentration between 30 and 60 min showed differences that ranged from -7% to 8% between the repeated studies. Graphical analysis to obtain the distribution volume revealed intrasubject values that ranged from -9% to 7% for the ratio of the distribution volume in BG to that in CBL. These studies demonstrate that in order to use 11C-Raclopride to measure an individual's change in relative dopamine concentration secondary to pharmacological or behavioral intervention, a change in striatal 11C-Raclopride binding in excess of 10% is required.
Lars Farde - One of the best experts on this subject based on the ideXlab platform.
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low convergent validity of 11c Raclopride binding in extrastriatal brain regions a pet study of within subject correlations with 11c flb 457
NeuroImage, 2021Co-Authors: Tove Freiburghaus, Lars Farde, Jonas Svensson, Pontus Plavensigray, J M Lundberg, Granville J Matheson, Simon CervenkaAbstract:Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test-retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centres. Instead, the medium affinity radioligand [11C]Raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]Raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]Raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]Raclopride and [11C]FLB 457 BPND extrastriatally (Pearson's R: 0.30 - 0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearson's R: 0.82 - 0.98). In comparison, correlations between repeated [11C]Raclopride measurements were low to moderate (Pearson's R: 0.28 - 0.75). These results are likely related to low signal to noise ratio of [11C]Raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]Raclopride should be interpreted with caution.
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low convergent validity of 11c Raclopride binding in extrastriatal brain regions a pet study of within subject correlations with 11c flb 457
bioRxiv, 2020Co-Authors: Tove Freiburghaus, Lars Farde, Jonas Svensson, Pontus Plavensigray, J M Lundberg, Granville J Matheson, Simon CervenkaAbstract:Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test-retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centres. Instead, the medium affinity radioligand [11C]Raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]Raclopride in extrastriatal regions in a pharmacological competition study. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]Raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]Raclopride and [11C]FLB 457 BPND extrastriatally (Pearsons R: 0.30 - 0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearsons R: 0.82 - 0.98). These results are likely related to low signal to noise ratio of [11C]Raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]Raclopride should be interpreted with caution.
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validity and reliability of extrastriatal 11c Raclopride binding quantification in the living human brain
NeuroImage, 2019Co-Authors: Jonas Svensson, Lars Farde, Christer Halldin, Martin Schain, Pontus Plavensigray, Simon Cervenka, Mikael Tiger, Magdalena Nord, J M LundbergAbstract:Abstract [11C]Raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]Raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]Raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]Raclopride: (i) To assess the validity of extrastriatal [11C]Raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. (ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model with cerebellum as reference. Quetiapine dosing was associated with decrease in [11C]Raclopride BPND in temporal cortex (18 ± 17% occupancy) and thalamus (20 ± 17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51 ± 4%). The mean absolute variation was 4–7% in the striatal regions, 17% in thalamus, and 13–59% in cortical regions. Our data indicate that [11C]Raclopride PET, quantified using cerebellum as reference, is not a suitable tool to measure D2/3R in extrastriatal regions.
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validity and reliability of extrastriatal 11c Raclopride binding quantification in the living human brain
bioRxiv, 2019Co-Authors: Jonas Svensson, Lars Farde, Christer Halldin, Martin Schain, Pontus Plavensigray, Simon Cervenka, Mikael Tiger, Magdalena Nord, J M LundbergAbstract:[ 11 C]Raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D 2/3 R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [ 11 C]Raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [ 11 C]Raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [ 11 C]Raclopride: i) To assess the validity of extrastriatal [ 11 C]Raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D 2/3 R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BP ND ) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [ 11 C]Raclopride BP ND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [ 11 C]Raclopride PET is not a suitable tool for D 2/3 R binding quantification in extrastriatal regions.
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Synthesis of ([(11)C]carbonyl)Raclopride and a comparison with ([(11)C]methyl)Raclopride in a monkey PET study.
Nuclear medicine and biology, 2015Co-Authors: Obaidur Rahman, Akihiro Takano, Nahid Amini, Kenneth Dahl, Naoki Kanegawa, Bengt Långström, Lars Farde, Christer HalldinAbstract:Abstract Introduction The selective dopamine D 2 receptor antagonist Raclopride is usually labeled with carbon-11 using [ 11 C]methyl iodide or [ 11 C]methyl triflate for use in the quantification of dopamine D 2 receptors in human brain. The aim of this work was to label Raclopride at the carbonyl position using [ 11 C]carbon monoxide chemistry and to compare ([ 11 C] carbonyl )Raclopride with ([ 11 C] methyl )Raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. Methods Palladium-mediated carbonylation using [ 11 C]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and ( S )-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([ 11 C] carbonyl )Raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (π-cinnamyl) chloride dimer as the palladium source. ([ 11 C] Methyl )Raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63min with an HRRT PET camera after intravenous injection of ([ 11 C] carbonyl )Raclopride and ([ 11 C] methyl )Raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3min prior to the PET scan. Binding potential (BP ND ) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. Results The target compound ([ 11 C] carbonyl )Raclopride was obtained with 50±5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [ 11 C]carbon monoxide was 65±5% and the specific radioactivity of the final product was 34±1GBq/μmol after a 50min of synthesis time. The radiochemical yield of ([ 11 C] methyl )Raclopride was in the same range as published previously i. e. 50–60% and specific radioactivity of those two batches which were used in the present PET study were 192GBq/μmol and 638GBq/μmol respectively after a synthesis time of 32min. In monkey PET studies, the percentage difference of BP ND in putamen was 11 C] carbonyl )Raclopride and ([ 11 C] methyl )Raclopride, respectively. The radiometabolite pattern was similar for both radioligands. Conclusion Raclopride was 11 C-labeled at the carbonyl position using a palladium-mediated [ 11 C]carbonylation reaction. A comparison between ([ 11 C] carbonyl )Raclopride and ([ 11 C] methyl )Raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([ 11 C] carbonyl )Raclopride showed similar results as for ([ 11 C] methyl )Raclopride. The PET studies were performed on 2 subjects.
Christer Halldin - One of the best experts on this subject based on the ideXlab platform.
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validity and reliability of extrastriatal 11c Raclopride binding quantification in the living human brain
NeuroImage, 2019Co-Authors: Jonas Svensson, Lars Farde, Christer Halldin, Martin Schain, Pontus Plavensigray, Simon Cervenka, Mikael Tiger, Magdalena Nord, J M LundbergAbstract:Abstract [11C]Raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]Raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]Raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]Raclopride: (i) To assess the validity of extrastriatal [11C]Raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. (ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model with cerebellum as reference. Quetiapine dosing was associated with decrease in [11C]Raclopride BPND in temporal cortex (18 ± 17% occupancy) and thalamus (20 ± 17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51 ± 4%). The mean absolute variation was 4–7% in the striatal regions, 17% in thalamus, and 13–59% in cortical regions. Our data indicate that [11C]Raclopride PET, quantified using cerebellum as reference, is not a suitable tool to measure D2/3R in extrastriatal regions.
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validity and reliability of extrastriatal 11c Raclopride binding quantification in the living human brain
bioRxiv, 2019Co-Authors: Jonas Svensson, Lars Farde, Christer Halldin, Martin Schain, Pontus Plavensigray, Simon Cervenka, Mikael Tiger, Magdalena Nord, J M LundbergAbstract:[ 11 C]Raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D 2/3 R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [ 11 C]Raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [ 11 C]Raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [ 11 C]Raclopride: i) To assess the validity of extrastriatal [ 11 C]Raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D 2/3 R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BP ND ) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [ 11 C]Raclopride BP ND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [ 11 C]Raclopride PET is not a suitable tool for D 2/3 R binding quantification in extrastriatal regions.
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Synthesis of ([(11)C]carbonyl)Raclopride and a comparison with ([(11)C]methyl)Raclopride in a monkey PET study.
Nuclear medicine and biology, 2015Co-Authors: Obaidur Rahman, Akihiro Takano, Nahid Amini, Kenneth Dahl, Naoki Kanegawa, Bengt Långström, Lars Farde, Christer HalldinAbstract:Abstract Introduction The selective dopamine D 2 receptor antagonist Raclopride is usually labeled with carbon-11 using [ 11 C]methyl iodide or [ 11 C]methyl triflate for use in the quantification of dopamine D 2 receptors in human brain. The aim of this work was to label Raclopride at the carbonyl position using [ 11 C]carbon monoxide chemistry and to compare ([ 11 C] carbonyl )Raclopride with ([ 11 C] methyl )Raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. Methods Palladium-mediated carbonylation using [ 11 C]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and ( S )-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([ 11 C] carbonyl )Raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (π-cinnamyl) chloride dimer as the palladium source. ([ 11 C] Methyl )Raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63min with an HRRT PET camera after intravenous injection of ([ 11 C] carbonyl )Raclopride and ([ 11 C] methyl )Raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3min prior to the PET scan. Binding potential (BP ND ) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. Results The target compound ([ 11 C] carbonyl )Raclopride was obtained with 50±5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [ 11 C]carbon monoxide was 65±5% and the specific radioactivity of the final product was 34±1GBq/μmol after a 50min of synthesis time. The radiochemical yield of ([ 11 C] methyl )Raclopride was in the same range as published previously i. e. 50–60% and specific radioactivity of those two batches which were used in the present PET study were 192GBq/μmol and 638GBq/μmol respectively after a synthesis time of 32min. In monkey PET studies, the percentage difference of BP ND in putamen was 11 C] carbonyl )Raclopride and ([ 11 C] methyl )Raclopride, respectively. The radiometabolite pattern was similar for both radioligands. Conclusion Raclopride was 11 C-labeled at the carbonyl position using a palladium-mediated [ 11 C]carbonylation reaction. A comparison between ([ 11 C] carbonyl )Raclopride and ([ 11 C] methyl )Raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([ 11 C] carbonyl )Raclopride showed similar results as for ([ 11 C] methyl )Raclopride. The PET studies were performed on 2 subjects.
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Synthesis of [(CO)-C-11]Raclopride and a Comparison with [(CH3)-C-11]Raclopride in a Monkey PET Study
Journal of Labelled Compounds and Radiopharmaceuticals, 2015Co-Authors: Obaidur Rahman, Akihiro Takano, Nahid Amini, Kenneth Dahl, Naoki Kanegawa, Bengt Långström, Lars Farde, Christer HalldinAbstract:Synthesis of [(CO)-C-11]Raclopride and a Comparison with [(CH3)-C-11]Raclopride in a Monkey PET Study
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Test-retest reproducibility of dopamine D_2/3 receptor binding in human brain measured by PET with [^11C]MNPA and [^11C]Raclopride
European Journal of Nuclear Medicine and Molecular Imaging, 2013Co-Authors: Fumitoshi Kodaka, Christer Halldin, Hiroshi Ito, Yasuyuki Kimura, Saori Fujie, Harumasa Takano, Hironobu Fujiwara, Takeshi Sasaki, Kazuhiko Nakayama, Lars FardeAbstract:Purpose Dopamine D_2/3 receptors (D_2/3Rs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D_2/3 ^HIGH), which has a high affinity for endogenous dopamine, and low-affinity state (D_2/3 ^LOW). The density of D_2/3 ^HIGH can be measured with ( R )-2-^11CH_3O- N -n-propylnorapomorphine ([^11C]MNPA), while total density of D_2/3 ^HIGH and D_2/3 ^LOW (D_2/3Rs) can be measured with [^11C]Raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential ( BP ) of [^11C]MNPA to that of [^11C]Raclopride ([^11C]MNPA/[^11C]Raclopride) may reflect the proportion of the density of D_2/3 ^HIGH to that of D_2/3Rs. In the caudate and putamen, [^11C]MNPA/[^11C]Raclopride reflects the proportion of the density of D_2 ^HIGH to that of D_2Rs. To evaluate the reliability of the PET paradigm with [^11C]MNPA and [^11C]Raclopride, we investigated the test-retest reproducibility of non-displaceable BP ( BP _ND) measured with [^11C]MNPA and of [^11C]MNPA/[^11C]Raclopride in healthy humans. Methods Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [^11C]MNPA and [^11C]Raclopride scans. BP _ND values in the caudate and putamen were calculated. Test-retest reproducibility of BP _ND of [^11C]MNPA and [^11C]MNPA/[^11C]Raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). Results The absolute variability of [^11C]MNPA BP _ND was 5.30 ± 3.96 % and 12.3 ± 7.95 % and the ICC values of [^11C]MNPA BP _ND were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [^11C]MNPA/[^11C]Raclopride was 6.11 ± 3.68 % and 11.60 ± 5.70 % and the ICC values of [^11C]MNPA/[^11C]Raclopride were 0.79 and 0.80 in the caudate and putamen, respectively. Conclusion In the present preliminary study, the test-retest reproducibility of BP _ND of [^11C]MNPA and of [^11C]MNPA/[^11C]Raclopride was reliable in the caudate and putamen.
