Evaluation of the automatic three-dimensional delineation of caudate and putamen for PET receptor occupancy studies

OBJECTIVE: PET receptor occupancy studies with a baseline study and an intervention study are increasingly used as an aid in dose-finding procedures for central nervous system drug development. The aim of this study was to evaluate, and confirm the feasibility of two automatic, paired, three-dimensional delineation methods of striatal structures (caudate and putamen) for the purposes of PET receptor occupancy studies. METHODS: The automatic extraction was done with the deformable surface models from PET binding potential images. The segmentation result of the baseline study was utilized for segmenting the intervention study. The methods were evaluated with Monte Carlo simulated phantom images, a test-retest dataset with 11C-raclopride, and two receptor occupancy datasets (11C-raclopride and 18F-SPA-RQ). With the test-retest dataset, the reproducibility (normalized absolute differences (NAD)) and reliability (intraclass correlation coefficient (ICC)) of binding potential values were assessed with the proposed methods designed specifically for receptor occupancy and compared with the manual segmentation. A similar comparison was also performed for the receptor occupancy estimates. RESULTS: In the test-retest dataset, the two automatic three-dimensional segmentation methods had mean NADs ranging from 2.44 to 5.11% and ICCs from 0.88 to 0.98. The corresponding values for the manual two-dimensional segmentation were 3.45 to 6.65% and 0.82 to 0.96 (NAD differences non-significant). The automatic methods also yielded similar receptor occupancy values to the manual segmentation method in a range of high and low occupancy values. CONCLUSION: We believe that the automated three-dimensional segmentation will be useful in enhancing the analysis of large-scale PET receptor occupancy studies with high-resolution scanners.     

Design and implementation of an automated partial volume correction in PET: application to dopamine receptor quantification in the normal human striatum

The considerable effort and potential lack of reproducibility of human-driven PET quantification and partial volume correction (PVC) can be alleviated by use of atlas-based automatic analysis. The present study examined the application of a new algorithm designed to automatically define 3-dimensional regions of interest (ROIs) and their effect on dopamine receptor quantification in the normal human brain striatum, both without and with PVC. Methods: A total of 90 healthy volunteers (age range, 18-46 y) received a single injection of (11)C-raclopride, and automatic segmentation of concomitant structural MR images was performed using a maximum-probability atlas in combination with a trained neural network. For each identified tissue segment considered homogeneous for the tracer (or volumes of interest [VOIs]), an a priori criterion based on minimum axial recovery coefficient (RC(zmin) = 50%, 75%, and 90%) was used to constrain the extent of each ROI. RESULTS: With ROIs essentially overlapping the entire VOI volume (obtained with RC(zmin) = 50%), the binding potential (BP(ND)) of (11)C-raclopride was found to be around 2.2 for caudate and 2.9 for putamen, an underestimation by 35% and 28%, respectively, according to PVC values. At increased RC(zmin), BP(ND) estimates of (11)C-raclopride were increased by 12% and 21% for caudate and 8% and 15% for putamen when the associated ROIs decreased to around 65% and 43% of total tissue volume (VOI) for caudate and 67% and 31% for putamen. After PVC, we observed relative increases in BP(ND) variance of 12% for caudate and 20% for putamen, whereas estimated BP(ND) values all increased to 3.4 for caudate and 4.0 for putamen, regardless of ROI size. Dopamine receptor concentrations appeared less heterogeneous in the normal human striatum after PVC than they did without PVC: the 25%-30% difference in BP(ND) estimates observed between caudate and putamen remained significant after PVC but was reduced to slightly less than 20%. Furthermore, the results were comparable with those obtained with a manual method currently in use in our laboratory. CONCLUSION: The new algorithm allows for traditional PET data extraction and PVC in an entirely automatic fashion, thus avoiding labor-intensive analyses and potential intra- or interobserver variability. This study also offers the first, to our knowledge, large-scale application of PVC to dopamine D(2)/D(3) receptor imaging with (11)C-raclopride in humans.     

A feasibility study of [11C]SA4503-PET for evaluating sigma1 receptor occupancy by neuroleptics: The binding of haloperidol to sigma1 and dopamine D2-like receptors

We investigated feasibility of positron emission tomography (PET) with [11C]SA4503 for evaluating the sigma1 receptor occupancy rate by neuroleptics. Haloperidol, which is well known to bind dopamine D2-like receptor (D2R) as well as to be a representative non-selective antagonist for sigma1 receptor (sigma1R), was selected as a model drug. Three healthy male subjects underwent 60-min [11C]raclopride-PET and 90-min [11C]SA4503-PET scans successively at a 120-min interval twice in a day for baseline measurement and on another day for haloperidol-loading measurement 16 hours after peroral administration of 3 mg of haloperidol. Binding potential (BP) of [11C]raclopride and [11C]SA4503 was quantitatively evaluated and the sigma1R and D2R occupancy rates were determined. D2R occupancy rates by haloperidol were 64% and 62% in the caudate and putamen, respectively, 16 h after the administration, while sigma1R occupancy rates were approximately 80% in all seven regions investigated including the caudate, putamen and cerebellum 18 h after the administration, suggesting that the sigma1R receptor occupancy rate by haloperidol was slightly larger than the D2R receptor occupancy rate. We concluded that [11C]SA4503-PET can be used for evaluating the sigma1R occupancy rates by neuroleptics or other drugs.     

Striatal D2 receptor availability after shunting in idiopathic normal pressure hydrocephalus.

Gait disturbance in idiopathic normal pressure hydrocephalus (iNPH) is reminiscent of parkinsonism. Our recent PET study showed reduction in postsynaptic D(2) receptor binding concomitant with a normality of presynaptic dopamine transporter binding. Here, we investigated the plasticity of D(2) receptor in treating iNPH patients with ventriculoperitoneal (VP) shunting using PET with (11)C-raclopride and discuss the contribution of D(2) receptor to the pathophysiology of iNPH. METHODS: Eight iNPH patients participated in this study. After evaluation of their neuropsychologic abilities, all patients underwent 3-dimensional MRI and quantitative PET measurements twice before and 1 mo after VP shunting. MRI-based morphometric analyses were performed to examine postoperative variations of the ventricles. Estimation of binding potential (BP) for (11)C-raclopride was based on Logan plot analysis. Region-of-interest analysis was used to examine changes in (11)C-raclopride BP in the striatum. A 2-tailed paired t test was used for evaluating changes in PET and MRI parameters between conditions, and correlation analysis was used to investigate clinicopathophysiologic relevance (clinical vs. in vivo findings). RESULTS: Clinical evaluation revealed significant recovery in a 5-m back-and-forth navigation test and an affect test and a mild increase in Mini-Mental State Examination scores after VP shunting. Significant postoperative increases in (11)C-raclopride BP were found in the nucleus accumbens and dorsal putamen, and the increases were significantly associated with emotional (Spearman rank r = 0.66, P < 0.05) and navigational improvement (r = 0.72, P < 0.05), respectively. The (11)C-raclopride BP increase in the striaum as a whole correlated significantly with improvement in general cognitive ability. There was a mild ventricular shrinkage after surgery, albeit there was no correlation of its size with clinical and PET parameters. CONCLUSION: Striatal upregulation of D(2) receptor after VP shunting is associated with amelioration of hypokinetic gait disturbance and anhedonic mentation in iNPH patients, indicating that the effect of VP shunting may reside in noninhibition of functionally suppressed D(2) receptor in the striatum. D(2) receptor responsiveness may indicate a mechanism for iNPH pathophysiology.     

Test–retest stability of cerebral A<Subscript>1</Subscript> adenosine receptor quantification using [<Superscript>18</Superscript>F]CPFPX and PET

PURPOSE: The goal of the present study was to evaluate the reproducibility of cerebral A1 adenosine receptor (A1AR) quantification using [18F]CPFPX and PET in a test-retest design. METHODS: Eleven healthy volunteers were studied twice. Eight brain regions ranging from high to low receptor binding were examined. [18F]CPFPX was injected as a bolus with subsequent infusion over 120 min. Various outcome parameters were compared based on either metabolite-corrected venous blood sampling [e.g. apparent equilibrium total distribution volume (DVt')] or a reference region [ratio of specific to non-specific distribution volume (BP2)]. RESULTS: Test-retest variability was low in the outcome measure BP2 (on average 5.9%) and moderate in DVt' (on average 13.2%). Regarding reproducibility, the outcome parameter BP2 showed an intra-class correlation coefficient (ICC) of 0.94 +/- 0.1. For DVt' the between-subject coefficient of variation (%CV) was similar to the within-subject %CV (around 10%), resulting in a poor ICC of 0.06 +/- 0.2. CONCLUSION: Our results suggest that quantification of [18F]CPFPX imaging is reproducible and reliable for PET studies of the cerebral A1AR. Among the outcome parameters the non-invasive measures were of superior test-retest stability over the invasive.     

Parametric mapping of binding in human brain of D2 receptor ligands of different affinities.

(11)C-Raclopride has been widely used for PET studies of dopamine D(2/3) receptors in human brain. The long half-life of (18)F may impart advantages to the novel moderate-affinity benzamide (18)F-desmethoxyfallypride and its high-affinity congener (18)F-fallypride for competition studies and for detection of extrastriatal binding. However, the in vivo kinetics of these compounds and the quantification approaches for parametric mapping of their specific bindings have not been systematically compared. METHODS: Dynamic emission recordings of the 3 tracers were obtained in groups of healthy subjects. A conventional model, graphical analysis using metabolite-corrected arterial inputs, and models with reference tissue inputs were used to calculate voxelwise parametric maps of the equilibrium distribution volume (V(d)) and the binding potential (BP) of the 3 radioligands in brain. To test for bias, voxelwise kinetic results were compared with those obtained by volume-of-interest (VOI) analysis. RESULTS: The V(d) and BP estimates obtained by VOI analysis did not differ from the mean of voxelwise estimates in the same striatal volumes. In striatum, the mean (18)F-desmethoxyfallypride BP ranged from 1.9 to 2.5, whereas the mean (11)C-raclopride BP ranged from 3 to 4, depending on the method used for calculation. In contrast, the mean BP of (18)F-fallypride ranged from 16 to 27 in striatum and could also be readily quantified in the thalamus. CONCLUSION: Reference tissue methods for the voxelwise calculation of binding parameters are suitable for parametric mapping of the 3 dopamine D(2/3) receptor ligands.     

Sigma1 and dopamine D2 receptor occupancy in the mouse brain after a single administration of haloperidol and two dopamine D2-like receptor ligands

We investigated sigma(1) and dopamine D(2) receptor occupancy in mouse brain after a single injection of haloperidol, nemonapride, or spiperone using [(11)C]SA4503 and [(11)C]raclopride, respectively. Co-injection of the three compounds significantly blocked the uptake of each radioligand. Six hours later, only haloperidol blocked [(11)C]SA4503 uptake, while all three reduced [(11)C]raclopride uptake. Sigma(1) receptor occupancy by haloperidol was reduced to 19% at day 2 when D(2) receptor occupancy disappeared. [(11)C]SA4503 would be applicable to the investigation of sigma(1) receptor occupancy of antispychotic drugs using PET.     

Age-related decline in dopamine transporter in human brain using PET with a new radioligand [18F]FE-PE2I

Objective

Dopamine transporter (DAT) density is considered as a marker of pre-synaptic function. Numerous neuroimaging studies have consistently demonstrated an age-related decrease in DAT density in normal human brain. However, the precise degree of the regional decline is not yet clear. The purpose of this study was to evaluate the effect of the normal aging process on DAT densities in human-specific brain regions including the substantia nigra and thalamus using positron emission tomography (PET) with [¹⁸F]FE-PE2I, a new PET radioligand with high affinity and selectivity for DAT.

Methods

Thirty-six healthy volunteers ranging in age from 22 to 80 years were scanned with PET employing [¹⁸F]FE-PE2I for measuring DAT densities. Region of interest (ROI)-based analysis was used, and ROIs were manually defined for the caudate, putamen, substantia nigra, thalamus, and cerebellar cortex. DAT binding was quantified using a simplified reference tissue model, and the cerebellum was used as reference region. Estimations of binding potential in the caudate, putamen, substantia nigra, and thalamus were individually regressed according to age using simple regression analysis. Estimates of DAT loss per decade were obtained using the values from the regression slopes.

Results

There were 7.6, 7.7, and 3.4 % per-decade declines in DAT in the caudate, putamen, and substantia nigra, respectively. By contrast, there was no age-related decline of DAT in the thalamus.

Conclusions

[¹⁸F]FE-PE2I allowed reliable quantification of DAT, not only in the caudate and putamen but also in the substantia nigra. From the results, we demonstrated the age-related decline in the caudate and putamen as reported in previous studies, and additionally for those in the substantia nigra for the first time.     

Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457--a test-retest analysis

[11C]FLB 457 is a radioligand for positron emission tomography (PET) that possesses high affinity to D2/D3 receptors. It has been suggested to be useful for quantification of low-density dopamine D2 receptor populations, e.g. in cortical and limbic brain areas. We explored the reproducibility of five methods for measuring extrastriatal D2-like receptor binding potential with [11C]FLB 457. Seven healthy male volunteers were examined twice with [11C]FLB 457 (high specific radioactivity) on the same day, at least 3 h apart. Four brain areas, frontal cortex, nucleus thalamus, temporal cortex and cerebellar cortex, were examined. Binding potentials (BPs) were derived from (1) a target to cerebellum distribution volume ratio, (2/3) two reversible reference tissue compartment models and (4) a transient equilibrium approach. For comparison, BP values were also calculated with the standard three-compartment kinetic model that does not assume a receptor-free reference region. The use of the standard three-compartment model did not result in reproducible BP estimates. The distribution volume (DV) ratio, reference tissue compartment models and the transient equilibrium method all had good to excellent intraclass correlation coefficients (ICCs) in the studied brain areas ranging from 0.56 to 0.93. Absolute variability was also relatively low, ranging from 5.3% to 10.4%. There were no marked differences in the ICC or absolute and relative variability between the four methods based on a reference tissue (cerebellum). In addition, we did not observe systematic differences in the BP between the first and the second scan. These data indicate that the reproducibility of the DV ratio, reference tissue models and the transient equilibrium method is good or excellent. However, each of these methods includes assumptions affecting their validity. Thus, the choice of method will be critically dependent on the purpose of the study.     

11C-雷氯必利的自动化制备及其在新生猪脑PET/CT显像的应用

目的自动化制备D2受体显像剂11 C-雷氯必利(11 C-raclopride),并应用于正常新生猪脑D2受体PET/CT显像。方法气相循环法合成11 C-碘甲烷(CH3I)为中间体制备11 C-raclopride,应用于正常新生猪脑PET/CT动态显像,绘制双侧基底节时间—活性动态曲线。结果制备11 C-raclopride最终产物14.6±3.6(8.8～15.0)mci,比活度68.8±20.9(39.0～86.8)GBq/μmol,放化纯度>99%。PET/CT显像示:3～5min基底节区放射性达高峰,双基底节显示清晰,放射性分布明显高于脑内其它部位;随后,基底节区放射性缓慢降低,30min达稳定水平。结论自动化制备11 C-raclopride的方法简便,过程容易控制,可应用于新生猪D2受体PET/CT显像,为缺氧缺血脑损伤D2受体功能状态的研究奠定基础。     

Test-retest reproducibility of extrastriatal dopamine D2 receptor imaging with [123I]epidepride SPECT in humans.

This study evaluated the test-retest reproducibility of D2 receptor quantification in the thalamus and temporal cortex using [123I]epidepride SPECT. METHODS: Ten healthy volunteers (4 men, 6 women; age range, 19-46 y) underwent 2 SPECT studies (interval, 2-26 d) using a bolus-plus-constant-infusion paradigm (bolus-to-infusion ratio = 6 h; infusion time = 9 h). Plasma clearance (in liters per hour) and free fraction (f1) of the parent tracer were measured. Radioactivity (in becquerels per gram) in the thalamus, temporal cortex, and cerebellum were normalized to the infusion rate (in becquerels per hour). Normalized striatal radioactivity was also measured to assess reproducibility in regions with a high density of receptors and better counting statistics. The outcome measures obtained were V3 (receptor density [Bmax]/equilibrium dissociation constant [KD]), V3' (f1 x Bmax/KD), and RT (specific-to-nondisplaceable tissue ratio). RESULTS: Test-retest variability and reliability (intraclass correlation coefficient) were 10.8% and 0.88, respectively, for plasma clearance and 15.3% and 0.77, respectively, for f1. The test-retest variability of brain-specific (target minus nondisplaceable) radioactivity was higher in the thalamus and temporal cortex than in the striatum, although reliability was comparable. Among the outcome measures, V3' showed better test-retest variability and reliability in the thalamus (13.3% and 0.75, respectively) and temporal cortex (13.4% and 0.86, respectively). CONCLUSION: Brain radioactivity was the main source of variability for quantification of extrastriatal D2 receptors with [123I]epidepride. The reproducibility of outcome measures in extrastriatal regions was good. However, because receptor density was lower in extrastriatal regions than in the striatum, the counting statistics in these regions were low and reproducibility was affected by the higher test-retest variability of brain-specific radioactivity. Compared with V3 and V3', RT showed less test-retest variability in the thalamus and temporal cortex but lower reliability. Moreover, measurement of RT may be affected by the presence of potential lipophilic metabolites entering the brain.     

Reproducibility of [11 C]FLB 457 binding in extrastriatal regions

Extrastriatal D2 dopamine receptors represent an important target of research into the pathophysiology and pharmacotherapy of psychiatric disorders. The high affinity radioligand [11C]FLB 457 makes possible the measurement of low concentrations of D2 receptors in extrastriatal regions using positron emission tomography (PET). The aim of this study was to assess the test/retest variability and reliability of [11C]FLB 457 binding using a reference tissue model. Eight healthy male subjects (aged 20-33 years) underwent two [11C]FLB 457 PET examinations. Radioactivity in the cerebellum was used as the reference. The binding potentials (BPs) for five cortical regions of interest (ROIs) were calculated using the reference tissue model. The BP was also calculated for each pixel in the form of parametric images. Reproducibility was assessed both for the ROI method and for the parametric images. The test/retest reproducibility for [11C]FLB 457 binding was good, with a mean variability ranging from 4.5% for the thalamus to 15.5% for the hippocampus. The parametric images also demonstrated good reproducibility. These results support the suitability of using [11C]FLB 457 for the quantitative evaluation of extrastriatal D2 receptors and for protocols requiring repeated measurements in the same individual.     

Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain.

Automated voxel-based or predefined volume-of-interest (VOI) analysis of rodent small-animal PET data is necessary for optimal use of information because the number of available resolution elements is limited. We have mapped metabolic ((18)F-FDG), dopamine transporter (DAT) (2'-(18)F-fluoroethyl(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]-octane-2-carboxylate [(18)F-FECT]), and dopaminergic D(2) receptor ((11)C-raclopride) small-animal PET data onto a 3-dimensional T2-weighted MRI rat brain template oriented according to the rat brain Paxinos atlas. In this way, ligand-specific templates for sensitive analysis and accurate anatomic localization were created. Registration accuracy and test-retest and intersubject variability were investigated. Also, the feasibility of individual rat brain statistical parametric mapping (SPM) was explored for (18)F-FDG and DAT imaging of a 6-hydroxydopamine (6OHDA) model of Parkinson's disease. METHODS: Ten adult Wistar rats were scanned repetitively with multitracer small-animal PET. Registrations and affine spatial normalizations were performed using SPM2. On the MRI template, a VOI map representing the major brain structures was defined according to the stereotactic atlas of Paxinos. (18)F-FDG data were count normalized to the whole-brain uptake, whereas parametric DAT and D(2) binding index images were constructed by reference to the cerebellum. Registration accuracy was determined using random simulated misalignments and vectorial mismatching. RESULTS: Registration accuracy was between 0.24 and 0.86 mm. For (18)F-FDG uptake, intersubject variation ranged from 1.7% to 6.4%. For (11)C-raclopride and (18)F-FECT data, these values were 11.0% and 5.3%, respectively, for the caudate-putamen. Regional test-retest variability of metabolic normalized data ranged from 0.6% to 6.1%, whereas the test-retest variability of the caudate-putamen was 14.0% for (11)C-raclopride and 7.7% for (18)F-FECT. SPM analysis of 3 individual 6OHDA rats showed severe hypometabolism in the ipsilateral sensorimotor cortex (P 相似文献   

Measurement of dopamine D2 receptors in living human brain using [11C]raclopride with ultra-high specific radioactivity

IntroductionHigh specific radioactivity is preferable in the measurement of neuroreceptor bindings with positron emission tomography (PET) because receptor occupancy by mixed cold ligand hampers the accurate estimation of receptor binding. Recently, we succeeded in synthesizing [¹¹C]raclopride, a dopamine D₂ receptor ligand, with ultra-high specific radioactivity, i.e., several thousand GBq/μmol. In the present study, we compared the [¹¹C]raclopride bindings to dopamine D₂ receptors between radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity in healthy human subjects.MethodsTwo PET studies using [¹¹C]raclopride with ultra-high specific radioactivity (4302–7222 GBq/μmol) or ordinary high specific radioactivity (133-280 GBq/μmol) were performed on different days in 14 healthy men. Binding potential (BP) was calculated by the simplified reference tissue method, peak equilibrium method, and area-under-the-curve method for each region-of-interest using time-activity data in the cerebellum as a reference brain region.ResultsBP values for radioligands with ultra-high specific radioactivity and ordinary high specific radioactivity calculated by the simplified reference tissue method were 4.06±0.29 and 4.10±0.25 in the putamen, 0.44±0.07 and 0.47±0.07 in the thalamus and 0.37±0.06 and 0.38±0.06 in the temporal cortex, respectively (mean±S.D.). No significant difference in BP was observed between ultra-high specific radioactivity and ordinary high specific radioactivity in any of the brain regions.ConclusionBP values of [¹¹C]raclopride with ultra-high specific radioactivity did not differ from those with ordinary high specific radioactivity in the measured brain regions, including striatal and extrastriatal regions.     

Assessment of 11C-PE2I binding to the neuronal dopamine transporter in humans with the high-spatial-resolution PET scanner HRRT.

The high-resolution research tomograph (HRRT), dedicated to brain imaging, may offer new perspectives for identifying small brain nuclei that remain neglected by the spatial resolution of conventional scanners. However, the use of HRRT for neuroimaging applications still needs to be fully assessed. The present study aimed at evaluating the HRRT for measurement of the dopamine transporter (DAT) binding to validate its quantification and explore the gain induced by the increased spatial resolution in comparison with conventional PET scanners. METHODS: Fifteen and 11 healthy subjects were examined using the selective DAT radioligand (11)C-PE2I with HRRT and HR+ scanners, respectively. Quantification of the DAT binding was assessed by the calculation of binding potential (BP) values using the simplified reference tissue model in anatomic regions of interest (ROIs) defined on the dorsal striatum and in a standardized ROI defined on the midbrain. RESULTS: Quantification of (11)C-PE2I binding to the DAT measured in the midbrain and striatum with both scanners at the same spatial resolution (smoothed HRRT images) exhibited similar BP values and intersubject variability, thus validating the quantification of DAT binding on the HRRT. For age-paired comparison, BP values of subjects examined with HRRT were significantly higher than those of the subjects examined with HR+. The increase ranged from 29% in the caudate and 35% in the putamen to 92% in the midbrain. The decline in DAT binding with age in the striatum was in good agreement between both scanners and literature, whereas no significant decrease in DAT binding with age was observed in the midbrain with either HRRT or HR+. CONCLUSION: HRRT allows quantitative measurements of neurotransmission processes in small brain nuclei and allows recovering higher values as compared with coarser spatial resolution PET scanners. High-spatial-resolution PET appears promising for a more accurate detection of neurobiologic modifications and also for the exploration of subtle modifications in small and complex brain structures largely affected by the partial-volume effect.     

Validation of an extracerebral reference region approach for the quantification of brain nicotinic acetylcholine receptors in squirrel monkeys with PET and 2-18F-fluoro-A-85380.

The aim of the present study was to explore the applicability of an extracerebral reference region for the quantification of cerebral receptors with PET. METHODS: Male squirrel monkeys underwent quantitative PET studies of cerebral nicotinic acetylcholine receptors (nAChRs) with 2-(18)F-fluoro-A-85380 (2-FA). Data from dynamic PET scans were analyzed with various compartment- and non-compartment-based models, including a simplified reference tissue model (SRTM). Nondisplaceable volume-of-distribution (VDnd) values were determined in regions of interest after the blockade of 2-FA-specific binding by nicotine infusion. Binding potential values, estimated with the cerebellum and muscle as reference regions, were compared and the reproducibility of measurements was determined. RESULTS: One- and 2-tissue-compartment modeling and linear graphic analysis provided similar total volume-of-distribution (VD(T)) values for each studied region. VD(T) values were high in the thalamus, intermediate in the cortex and midbrain, and low in the cerebellum and muscle, consistent with the distribution pattern of nAChR containing alpha(4) and beta(2) receptor subunits (alpha(4)beta(2)*). The administration of nicotine at 2 mg/kg/d via an osmotic pump resulted in a nearly complete saturation of 2-FA-specific binding and led to very small changes in volumes of distribution in the cerebellum and muscle (-9% +/- 4% [mean +/- SEM] and 0% +/- 6%, respectively), suggesting limited specific binding of the radioligand in these areas. VD(T) measured in muscle in 15 monkeys was reasonably constant (3.0 +/- 0.2, with a coefficient of variation of 8%). VDnd in studied brain regions exceeded VD(T) in muscles by a factor of 1.3. With this factor and with muscle as a reference region, BP* values calculated for studied brain regions with the SRTM were in good agreement with those obtained with the cerebellum as a reference region. Significant correlations were observed between BP* values estimated with these 2 approaches. The reproducibilities of BP* measurements obtained with the 2 methods were comparable, with coefficients of variation of less than 11% and 13% for the thalamus and the cortex, respectively. CONCLUSION: These results suggest that the accurate quantification of nAChRs can be performed with 2-FA and a reference region outside the brain, providing a novel approach for the quantification of brain receptors when no suitable cerebral reference region is available.     

Carbon-11 epidepride: a suitable radioligand for PET investigation of striatal and extrastriatal dopamine D2 receptors.

Epidepride [(S)-(-)-N-([1-ethyl-2-pyrrolidinyl]methyl)-5-iodo-2,3-dimethoxybenza mide] binds with a picomolar affinity (Ki = 24 pM) to the dopamine D2 receptor. Iodine-123-labeled epidepride has been used previously to study striatal and extrastriatal dopamine D2 receptors with single photon emission computed tomography (SPECT). Our aim was to label epidepride with carbon-11 for comparative quantitative studies between positron emission tomography (PET) and SPECT. Epidepride was synthesized from its bromo-analogue FLB 457 via the corresponding trimethyl-tin derivative. In an alternative synthetic pathway, the corresponding substituted benzoic acid was reacted with the optically pure aminomethylpyrrolidine-derivative. Demethylation of epidepride gave the desmethyl-derivative, which was reacted with [11C]methyl triflate. Total radiochemical yield was 40-50% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was 37-111 GBq/micromol (1,000-3,000 Ci/mmol). Human postmortem whole-hemisphere autoradiography demonstrated dense binding in the caudate putamen, and also in extrastriatal areas such as the thalamus and the neocortex. The binding was inhibited by unlabeled raclopride. PET studies in a cynomolgus monkey demonstrated high uptake in the striatum and in several extrastriatal regions. At 90 min after injection, uptake in the striatum, thalamus and neocortex was about 11, 4, and 2 times higher than in the cerebellum, respectively. Pretreatment experiment with unlabeled raclopride (1 mg/kg) inhibited 50-70% of [11C]epidepride binding. The fraction of unchanged [11C]epidepride in monkey plasma determined by a gradient high performance liquid chromatography (HPLC) method was about 30% of the total radioactivity at 30 min after injection of [11C]epidepride. The availability of [11C]epidepride allows the PET-verification of the data obtained from quantitation studies with SPECT.     

SIC, an intracerebral beta(+)-range-sensitive probe for radiopharmacology investigations in small laboratory animals: binding studies with (11)C-raclopride.

Our aim was to show the ability of a recently developed beta(+)-range-sensitive intracerebral probe (SIC) to measure, in vivo, the binding of radioligands in small animals. METHODS: The potential of the device for pharmacokinetic studies was evaluated by measurement of the dynamic striatal binding of (11)C-raclopride, a well-documented D(2) dopaminergic receptor ligand, in rat brain after intravenous injection of the labeled compound. The effects of preinjection of the unlabeled ligand (raclopride, 2 mg/kg intravenously) and of increasing the synaptic dopamine level (amphetamine treatment, 1 mg/kg intravenously) or of depleting synaptic dopamine (reserpine pretreatment, 5 mg/kg intraperitoneally) on in vivo (11)C-raclopride binding were monitored by SIC. RESULTS: The radioactivity curves measured as a function of time were reproducible and consistent with previous studies using PET imaging (ratio of striatum to cerebellum, 2.6 +/- 0.3 after 20 min). Further studies showed significant displacement of (11)C-raclopride by its stable analog. Finally, the device proved its capacity to accurately detect changes in (11)C-raclopride binding after a sudden (amphetamine) or a gradual (reserpine) modulation of endogenous dopamine levels. CONCLUSION: These results show that the new device can monitor binding of PET ligands in anesthetized rodents in vivo, with high temporal resolution.     

PET evaluation of the relationship between D2 receptor binding and glucose metabolism in patients with parkinsonism

OBJECTIVE: To clarify the relationship between D2 receptor binding and the cerebral metabolic rate for glucose (CMRGlu) in patients with parkinsonism, we simultaneously measured both of these factors, and then compared the results. METHODS: The subjects consisted of 24 patients: 9 with Parkinson's disease (PD), 3 with Juvenile Parkinson's disease (JPD), 9 with multiple system atrophy (MSA), and 3 with progressive supranuclear palsy (PSP). The striatal D2 receptor binding was measured by the C-11 raclopride transient equilibrium method. CMRGlu was investigated by the F-18 fluorodeoxyglucose autoradiographic method. RESULTS: The D2 receptor binding in both the caudate nucleus and putamen showed a positive correlation with the CMRGlu in the PD-JPD group, but the two parameters demonstrated no correlation in the MSA-PSP group. The left/right (L/R) ratio of D2 receptor binding in the putamen showed a positive correlation with that of CMRGlu in the MSA-PSP group, while the two demonsrated no correlation in the PD-JPD group. CONCLUSION: Our PET study showed striatal D2 receptor binding and the CMRGlu to be closely related in patients with parkinsonism, even though the results obtained using the L/R ratios tended to differ substantially from those obtained using absolute values. The reason for this difference is not clear, but this finding may reflect the pathophysiology of these disease entities.     

Quantitative analysis of norepinephrine transporter in the human brain using PET with (S,S)-18F-FMeNER-D2

(S,S)-18F-FMeNER-D2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. METHODS: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-18F-FMeNER-D2. Binding potential relative to nondisplaceable binding (BP(ND)) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. RESULTS: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BP(ND) values by the indirect kinetic method were 0.54 +/- 0.19 and 0.35 +/- 0.25 in the thalamus and locus coeruleus, respectively. BP(ND) values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r = 0.81-0.92). CONCLUSION: The regional distribution of (S,S)-18F-FMeNER-D2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.