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. Author manuscript; available in PMC: 2013 Sep 1.
Published in final edited form as: Synapse. 2012 May 15;66(9):770–780. doi: 10.1002/syn.21566

Characterization of Extrastriatal D2 In Vivo Specific Binding of [18F](N-methyl)benperidol Using PET

Sarah A Eisenstein a, Jon M Koller a, Marilyn Piccirillo a, Ana Kim a, Jo Ann V Antenor-Dorsey a, Tom O Videen b,c, Abraham Z Snyder c, Morvarid Karimi b, Stephen M Moerlein c,d, Kevin J Black a,b,c,e, Joel S Perlmutter b,c,e,f,g, Tamara Hershey a,b,c
PMCID: PMC3389593  NIHMSID: NIHMS382844  PMID: 22535514

INTRODUCTION

Alterations of striatal and extrastriatal concentrations of the dopaminergic D2 receptor family, including subtypes D2 (D2R) and D3 (D3R), may play a role in the pathophysiology or treatment of movement and psychiatric disorders including Parkinson disease (Kaasinen et al., 2000a; Kaasinen et al., 2003; Smith and Villalba, 2008), dystonia (Karimi et al., 2011; Perlmutter et al., 1997), Huntington's disease (Pavese et al., 2003), restless legs syndrome (Cervenka et al., 2006; Connor et al., 2009), schizophrenia (Kegeles et al., 2010), social phobia (Schneier et al., 2000) and Tourette syndrome (Gilbert et al., 2006; Steeves et al., 2010). PET imaging with dopamine receptor radioligands provides an in vivo method to investigate such alterations. The most commonly used PET radioligands for the measurement of the D2 family of receptors include [11C] raclopride, [18F]fallypride and [11C]FLB 457. However, the disadvantages of using these radioligands is that they have near equal affinity for both D2R and D3R subtypes (Elsinga et al., 2006; Halldin et al., 1995; Mukherjee et al., 1999) and competition from endogenous dopamine may alter their uptake and retention in brain (Chou et al., 2000; Cropley et al., 2008; Dewey et al., 1992; Dewey et al., 1993; Montgomery et al., 2007; Riccardi et al., 2006; Seeman et al., 1989). These characteristics can be exploited in some experimental designs to measure endogenous dopamine release, but confound interpretation of specific binding levels since the PET measurement may reflect both the binding potential of D2R and D3R subtypes and levels of endogenous dopamine.

Although pharmacologic distinction between D2R and D3R subtypes of the dopamine D2 receptor family has been accomplished only recently, the DNA and mRNA that code for these proteins are quite distinct (Chien et al., 2010; Gingrich and Caron, 1993; Sokoloff et al., 1990). Post-mortem radioligand receptor autoradiography of D2R and D3R in the human brain reveal different receptor binding site patterns throughout the brain (Beaulieu and Gainetdinov, 2011; Hall et al., 1996a, b; Murray et al., 1994). Receptor distribution and mRNA expression levels in humans and rodents as determined by receptor autoradiography and in situ hybridization indicate that D2R is distributed heterogeneously throughout the brain; high levels of D2R occur in the dorsal striatum and pole of the nucleus accumbens as well as extrastriatal and cortical regions whereas D3R is highly distributed in limbic areas including the shell of the nucleus accumbens (Hall et al., 1996a, b; Missale et al., 1998; Sokoloff et al., 1992b; Vallone et al., 2000, Xu et al., 2010). However, recent autoradiography data from aged human brains demonstrate that D3R are distributed extensively throughout the striatum (Xu et al., 2011). Therefore, interpretation of previous D2/D3R distribution ratio reports should be viewed with caution; conflicting findings such as these indicate the need for in vivo study of D2R and D3R with PET radioligands specific for D2R or D3R in humans.

The differences in regional binding patterns of the D2R subtypes indicate that D2R and D3R likely play different roles in reward, cognition, movement and psychiatric disorders. For example, abnormalities in striatal D3R may play a key role in the pathophysiology of dystonia (Karimi et al., 2011). Notably, antipsychotic drugs have a higher affinity for D2R over D3R (Civelli et al., 1993; Sokoloff et al., 1992), suggesting a larger role for the D2R subtype in neuropsychiatric disorders, or, alternatively, that the D3 subtype may represent a relatively unexplored therapeutic target for D3-selective antagonist antipsychotics. Currently, the relatively modestly D3-preferring PET radiotracer and dopamine agonist [11C]-PHNO has been used to measure D3 specific receptor types (Gallezot et al., 2011; Girgis et al., 2011; Tziortzi et al., 2011). Improved distinction between D2R and D3R binding in striatal and extrastriatal regions via PET imaging would provide a valuable clinical research tool for in vivo study of neuropsychiatric disorders.

[18F]N-methylbenperidol ([18F]NMB) is a PET radioligand developed to measure D2R. It is an analog of the dopamine receptor antagonist benperidol of the butyrophenone structural class, has been clinically used as an antipsychotic drug (Reynolds, 1993), and has high affinity and selectivity for D2R (Karimi et al., 2011; Moerlein et al., 1995;, Suehiro et al., 1990). These latter characteristics have made butyrophenones compounds of interest in the search for PET dopamine receptor radioligands (Arnett et al., 1986; Moerlein et al, 1986, 1992, 1995; Suehiro et al., 1990). Selectivity of [18F]NMB and its analogues for D2 receptors over D1, serotonergic and adrenergic receptors has been demonstrated in vivo in baboon and in vitro in mice by unaltered striatal uptake after pretreatment with unlabeled receptor-specific antagonists and by displacement with unlabeled D2 antagonists (Arnett et al., 1985; Moerlein et al., 1995, 1997; Suehiro et al., 1990) [18F]NMB has more than 200-fold higher affinity for D2R than D3R, as recently demonstrated by in vitro radioligand binding assays in transfected cells that express D2 and D3 receptors (Karimi et al., 2011). [18F]NMB reversibly binds to D2R's (Moerlein et al., 1995, 1997; Suehiro et al., 1990) and resists competition from endogenous dopamine release, as demonstrated by lack of displacement by high dose intravenous amphetamine (Moerlein et al., 1997). Thus, [18F]NMB is an excellent candidate radioligand for unambiguous PET quantification of the D2R subtype in brain. Previous research demonstrated [18F]NMB's ability to specifically bind to D2R in striatum (Antenor-Dorsey et al., 2008; Karimi et al., 2011). However, PET measures of extrastriatal D2R specific binding with [18F]NMB has not yet been quantified. Given the importance of extrastriatal D2R binding in neuropsychiatric and movement disorders, it is necessary to determine whether PET using [18F]NMB can reliably measure D2R specific binding in these regions. We now report such PET imaging studies in healthy adults.

MATERIALS AND METHODS

Human subjects

MR and PET scans were obtained from 14 healthy control subjects, ages 29-80 years (6 men, ranging from 29-80 years old; mean age = 55.3, S.D. = 20.6; 8 women, ranging from 43-71 years old; mean age = 61.1, S.D. = 8.9). Subjects were screened for psychiatric and neurologic disorders. All procedures were approved by Washington University's Human Research Protection Office and the Radioactive Drug Research Committee. All subjects provided informed written consent.

MRI acquisition

Each subject underwent MRI scans in a Siemens Vision 1.5T Magnetom scanner with an MPRAGE pulse sequence (TR=9.7msec, TE=4 msec, flip angle = 12, time= 6:36, pixel size= 1 × 1 × 1.25 mm).

Radiopharmaceutical preparation

[18F]Fluoride was produced by the 18O(p, n) 18F nuclear reaction induced on an isotopically enriched [18O]water target using the Washington University JSW BC-16/8 cyclotron. A three-step reaction sequence was used to synthesize [18F]NMB from [18F]fluoride (Moerlein et al., 1992). Radiochemical purity of the final product was over 95% and end-of-synthesis specific activity was at least 2000 Ci/mmol (74 TBq/mmol) (Moerlein et al., 1992). [18F]NMB was reformulated in ethanol 0.9% Sodium Chloride Injection, USP (1/10 v/v) and sterilized by terminal filtration prior to human administration.

PET acquisition

A Siemens/CTI ECAT 953B scanner was used to acquire scans in three-dimensional mode (septa retracted) (Mazoyer et al., 1991; Spinks et al., 1992), allowing for reconstruction of 31 simultaneous planes 3.38 mm apart. Transaxial reconstructed resolution was 4.9 mm FWHM at the center of each plane and axial resolution was 5.2 mm. We used a model-based scatter-correction algorithm that was implemented and quantitatively validated for this scanner (Ollinger, 1996).

The subject's head was positioned to obtain scans from the most dorsal regions of the striatum to caudal cerebellum and was stabilized with a polyform plastic mask. Intravenous injection of [18F]NMB (185-259 MBq over 30 s) into an arm vein was done through a 20-gauge catheter. Dynamic PET images were obtained in all subjects for 120 min beginning with radioligand injection (10 1-min frames followed by 22 5-min frames (n =5) or 3 1-min frames followed by 4 2-min frames, 3 3-min frames and 20 5 min frames (n = 9)). Subjects were observed closely throughout the PET scan.

Image analysis

For each subject, the dynamically acquired PET image frames were mutually coregistered to each other and to the individual's MPRAGE image using a novel method with low measured error (see Supporting Information). MPRAGE atlas transformation was computed by 12-parameter affine registration to a target image representing Talairach atlas space (Talairach and Tournoux, 1988) as defined by the “SN” method of Lancaster et al. (1995). The atlas transformation for each PET frame then was computed by composition of transforms (frame→MPRAGE × MPRAGE→atlas) and the PET data were resampled to (2mm)3 atlas space (Hershey et al., 2003).

For each subject, we created an image of decay-corrected PET activity summed from 60-120 minutes after [18F]NMB injection, normalized to the mean in whole cerebellum. These images were averaged across subjects to create a composite image of averaged NMB activity during this time. Using a peak-finding algorithm, we identified regions of peak activity in the composite image mandating that local peak voxels must be separated by at least 6mm (3 voxels) and accepting only peaks that were at least 20% higher in intensity than the normalized cerebellar reference region. These parameters increased certainty that the generated list of peak regions were reasonably independent of each other. We identified anatomic labels for the peaks using the Talairach Client software (www.talairach.org) (Lancaster et al., 1997, 2000; Talairach and Tournoux, 1988). Peak regions of radioactivity were interpreted to indicate increased D2R specific binding, assuming constant non-specific uptake across the brain.

As a complementary approach, D2R binding (BPND) was quantified in a priori defined ROIs. The neuroimaging software Freesurfer (http://surfer.nmr.mgh.harvard.edu/) was used for segmentation of subcortical deep nuclei, frontal and temporal cortical regions, and cerebellum on individual MRs. Caudate, putamen, nucleus accumbens (NAc), thalamus, amygdala, hippocampus, various temporal and frontal cortical regions and cerebellum were identified. The cerebellum region included all gray and white matter of both hemispheres. The hypothalamus and midbrain regions were manually traced on individual MPRAGEs and added to this group of a priori ROIs. The hypothalamus was continuously traced, beginning where the optic tract merged with the optic chiasm and ending where pons was absent but mammillary bodies were present on coronal slices. The midbrain was traced on axial slices at the level of the superior colliculus, ventral to corticospinal and corticobulbar tracts and dorsally to the raphe nuclei and included substantia nigra and red nucleus regions. We eroded several structures to minimize partial volume effects on the regional PET measurements of radioactivity. For the caudate, putamen, thalamus and hippocampus regions, we combined a gaussian smoothing filter with thresholding to erode approximately one voxel from the surface of the original region. For the amygdala, we eroded one voxel from the edge on each axial slice. In this way, approximately 2 mm was removed from the surface of ROIs (Figure 1). Hypothalamus, substantia nigra, nucleus accumbens, frontal and temporal cortical ROIs were not large or thick enough to erode in this manner.

Figure 1.

Figure 1

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Visualization of target regions for BPND analysis. Target ROIs (A-E) for one representative individual are overlaid on an MRI in axial and coronal views. The cerebellar reference region is depicted in F. To control for partial volume effects, ROIs were eroded when possible. Light blue coloring indicates original, uneroded regions as defined by FreeSurfer or manual tracing. Dark blue coloring indicates eroded regions. BPND's were obtained from eroded areas in all ROIs except for nucleus accumbens, hypothalamus, midbrain, and cortical regions. Sup Temp Sulcus, banks of superior temporal sulcus. rAnt Cing Cortex, rostral anterior cingulate cortex. Trans Temp Gyrus, transverse temporal gyrus. mOrbitofrontal Cortex, medial orbitofrontal cortex.

The Freesurfer- and manually defined ROIs and the cerebellar reference region were resampled in atlas space and decay-corrected tissue activity curves were extracted for each subject from the dynamic PET data. BPND was calculated for each ROI.

Quantitative analysis

[18F]NMB BPND's for each ROI for each subject were calculated from the PET data using the Logan graphical method with cerebellum as reference region (Logan et al., 1996) as previously described (Antenor-Dorsey et al., 2008). Only regions with BPND's greater than 0.1 were included in the analysis. Slopes were calculated from Logan plot points for the data acquired 60-120 min after radiotracer injection.

Kinetic analysis

In a separate analysis of extrastriatal regions, BPND's calculated with the Logan graphical method with a reference region were compared with those calculated with an explicit three-compartment tracer kinetic model using arterial blood measurements for the input function as well as with the Logan graphical method also using an arterial input function. Four extrastriatal regions that represent high and low BPND were selected for comparison among the three methods in 8 unique human subjects (4 male, 4 female, aged 31-71 years) who were included in a similar comparison of striatal BPND estimation methods (Antenor-Dorsey et al., 2008). These extrastriatal regions included thalamus, amygdala, rostral anterior cingulate cortex, and medial orbitofrontal cortex. MRI, PET, and image analyses were performed as described above and time-activity curves were generated for each ROI for each subject. Data from 60-120min post-injection was used as the standard interval for the linear regression. Otherwise, the comparison among the three methods was carried out as described in Antenor-Dorsey et al. (2008). Importantly, for the 3-compartment model, we calculated the BPND by the ratio of the combined forward rate (k3) constant to the dissociation rate constant (k4) and did not use a brain reference region.

Statistical analysis

BPND's were averaged across subjects for each ROI for statistical analysis. One-sample t-tests or, in the case of non-normally distributed data, one-sample Wilcoxon signed-rank tests were used to determine whether the mean specific D2R binding (BPND) in each ROI was significantly different from zero. Striatal and extrastriatal mean BPND's were analyzed for differences among regions by Friedman nonparametric repeated measures ANOVA followed by Dunn's post hoc multiple comparisons. Differences in BPND's between men and women were analyzed with Student's t-tests or Mann-Whitney comparisons for each ROI. Correlations between regional BPND's and age were performed with Pearson's r and Spearman's rho for normally distributed and nonparametric data, respectively. If these correlations were significant, volume was controlled for in partial correlations between age and BPND. Differences among methods for measuring BPND were analyzed by Friedman nonparametric repeated measures ANOVA followed by Dunn's post hoc multiple comparisons. Correlations between these BPND calculation methods were performed with Spearman's rho. Results were deemed significant at α ≤ 0.05.

RESULTS

Regional [18F]NMB activity peaks

Several regions on the composite image had relatively high concentrations of radioactivity compared to the reference region. These regions included putamen (maximum peak = 513% greater intensity than reference region), caudate (451%), thalamus (72%), midbrain (65%), parahippocampal gyrus (54%), hippocampus (51%), and temporal cortex (42%) (Figure 2).

Figure 2.

Figure 2

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Main results of the radioactivity peak analysis (n = 14). A peak analysis identified brain regions with high radioactivity counts in PET images including (A) striatal areas, (B) thalamus and hippocampus, (C) midbrain and (D) temporal cortex. Note the decrease in intensity threshold necessary to identify peaks (dark red, arrows) in extrastriatal regions (color bar on right side of each PET image). Mean PET counts in the cerebellar reference region was 1.

[18F] Time-activity curves

Time-activity curves over the course of 120 min for each target region were compared to the cerebellar reference region in each subject. Data for left and right hemispheres were pooled. Striatal curves show rapid uptake and then steady but slow decline in radioactivity over time. By contrast, [18F] uptake in extrastriatal regions is much lower relative to striatal regions although it is consistently higher than in the cerebellar reference region after achieving peak radioactivity. Representative plots from one subject are depicted in Figure 3.

Figure 3.

Figure 3

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Radioactivity levels by region over scan time. NMB activity over time of the PET scan is shown in one representative subject for (A) striatal ROIs, (B) subcortical extrastriatal ROIs and (C) cortical ROIs relative to the cerebellar reference region. Sup Temp Sulcus, banks of superior temporal sulcus. rAnt Cing Cortex, rostral anterior cingulate cortex. Trans Temp Gyrus, transverse temporal gyrus. mOrbitofrontal Cortex, medial orbitofrontal cortex.

Binding potential

Left and right BPND values for each ROI were averaged for each individual. Mean BPND's for eroded regions were greater than those for uneroded ROIs, indicating that partial volume effects of surrounding tissue were successfully reduced by erosion (Figure 1). For each ROI, mean eroded BPND was significantly greater than 0 (p < 0.001 for all comparisons), reflecting D2R specific binding relative to the cerebellum. Repeated measures ANOVA revealed significant differences in BPND's among all striatal regions (X22, N=14 = 28, p < 0.0001; p < 0.05 for all post hoc comparisons) (Figure 4a). Friedman repeated measures ANOVA revealed significant differences in BPND's among subcortical extrastriatal regions (X24, N=14 = 29.03, p < 0.0001) (Figure 4b). Thalamic BPND exceeded hippocampal BPND (Dunn post test, p < 0.001) and midbrain BPND (p < 0.05). Amygdala BPND was significantly greater than hippocampal BPND (p < 0.001) and midbrain BPND (p < 0.01). Friedman repeated measures ANOVA revealed significant differences in BPND's among cortical regions (X24, N=14 = 37.03, p < 0.0001) (Figure 4c). Insula BPND exceeded transverse temporal gyrus BPND (Dunn post test, p < 0.001) and medial orbitofrontal cortex BPND (p < 0.001). Banks of the superior temporal sulcus BPND was significantly greater than transverse temporal gyrus BPND (p < 0.05) and medial orbitofrontal cortex BPND (p < 0.05). No further significant differences in BPND's among extrastriatal regions were found.

Figure 4.

Figure 4

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Analyses of ROI BPND's as estimated by the Logan graphical method with cerebellum as a reference region. BPND's (mean ± S.D., n = 14) differed between and within (A) striatal,(B) extrastriatal subcortical and (C) cortical regions. Note the approximately 10-fold difference in scale between striatal and extrastriatal binding regions. NAc, nucleus accumbens. Sup Temp Sulcus, banks of superior temporal sulcus. rAnt Cing Cortex, rostral anterior cingulate cortex. Trans Temp Gyrus, transverse temporal gyrus. mOrbitofrontal Cortex, medial orbitofrontal cortex. *, ***, p < 0.05, p < 0.001 relative to other striatal regions; ###, p < 0.001 relative to hippocampus; †, ††, p < 0.05, p < 0.01 relative to midbrain; $, $$$, p < 0.05, p < 0.001 relative to transverse temporal gyrus; @, @@@, p < 0.05, p < 0.001 relative to medial orbitofrontal cortex.

Correlations

BPND's for putamen, caudate and NAc regions negatively correlated with age (p ≤ 0.02 for all striatal regions) (Figure 5). These correlations remained significant after controlling for volume of each ROI (p < 0.05 for all partial correlations). Age did not correlate significantly with BPND in any of the extrastriatal subcortical or cortical ROIs whether eroded or uneroded (subcortical: -0.21 ≤ r14 ≤ 0.51, p ≥ 0.06; cortical: -0.39 ≤ r14 ≤ -0.14, p ≥ 0.18).

Figure 5.

Figure 5

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Relationship between age and BPND. Age was negatively correlated with D2R BPND's in striatal regions including putamen (r14 = -0.81, p < 0.001), caudate (r14 = -0.89, p < 0.001) and nucleus accumbens (r14 = -0.63, p < 0.05).

Sex differences

BPND's did not differ between men and women for any ROI (p ≥ 0.35 for all comparisons).

Comparison of BPND estimation methods

Values for left and right hemisphere BPND estimates were averaged for all extrastriatal regions, except in the case of two subjects whose low tracer uptake in rostral anterior cingulate cortex and medial orbitofrontal cortex precluded adequate model fits in one hemisphere. In these cases, values from only one hemisphere were included in the comparisons. Mean BPND estimates for each ROI are shown in Table 1. For thalamus, (X23, N=8 = 13.61, p = 0.0001) the kinetic method BPND calculations were significantly greater than those of the graphical method with arterial input (p < 0.01) but not with cerebellum as a reference region (p > 0.05). Thalamic BPND's calculated by the two graphical methods did not significantly differ from each other. For amygdala, there was a main effect of type of method (X23, N=8 = 5.87, p < 0.05) but post hoc comparisons did not reveal significant pairwise differences among the three methods. For rostral anterior cingulate cortex (X23, N=8 = 13.86, p < 0.001), kinetic method BPND estimates were significantly greater than those of the graphical method with an arterial input (p < 0.01) and with cerebellum as a reference region (p < 0.05). Rostral anterior cingulate cortex BPND's calculated by the two graphical methods did not significantly differ from each other. For medial orbitofrontal cortex (X23, N=8 = 10.89, p = 0.001), kinetic method BPND estimates were significantly greater than those of the graphical method with an arterial input (p < 0.05) and with cerebellum as a reference region (p < 0.05). No differences between BPND estimation methods were otherwise observed for medial orbitofrontal cortex. As shown in Table 2, BPND's as estimated by all methods in all ROI's were strongly and positively correlated.

Table 1.

Comparison of BPND estimates computed by three methods (n = 8).

Region Kinetic Method with Arterial Input Logan Graphical Method with Arterial Input Logan Graphical Method with Reference Region
Thalamus Mean 0.51a 0.46 0.47
SD 0.09 0.09 0.09
SE 0.03 0.03 0.03
Amygdala Mean 0.51 0.45 0.48
SD 0.14 0.08 0.08
SE 0.05 0.03 0.03
Rostral Anterior Cingulate Cortex Mean 0.15a,b 0.09 0.09
SD 0.07 0.06 0.06
SE 0.02 0.02 0.02
Medial Orbitofrontal Cortex Mean 0.15a,b 0.08 0.08
SD 0.12 0.08 0.07
SE 0.04 0.03 0.02
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a

significantly different from BPND as estimated by graphical method with arterial input, p < 0.05.

b

significantly different from BPND as estimated by graphical method with reference region, p < 0.05

Table 2.

Correlation coefficients, r, between the three methods for BPND estimation (n = 8).

Kinetic Method/Graphical Method with Arterial Input Kinetic Method/ Graphical Method with Reference Region Graphical Method with Arterial Input/Graphical Method with Reference Region
Region r r r
Thalamus 0.89** 0.89** 1.00***
Amygdala 0.78* 0.69† 0.97***
Rostral Anterior Cingulate Cortex 0.83* 0.86* 0.99***
Medial Orbitofrontal Cortex 0.97*** 0.90** 0.95**
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*

p < 0.05

**

p < 0.01

***

p < 0.001, Spearman rho

†

p = 0.07

DISCUSSION

Our study demonstrates that PET measures using [18F]NMB, a radioligand highly selective for D2R (Karimi et al., 2011), can quantify regionally selective binding in striatal and extrastriatal regions. We used two methods, radioactivity peak analysis and BPND quantification in a priori-selected ROIs, to assess the ability of [18F]NMB to detect selective D2R binding in extrastriatal regions. These methods yielded comparable results: the regions in which peak [18F]NMB activity was detected are, for the most part, consistent with the rank order of the BPND measures obtained from these regions. The largest radioactivity peaks occurred in striatal regions and lower intensity peaks were found in extrastriatal subcortical regions (Figure 2). BPND's, which reflect the density of available receptors and affinity of the radioligand to the receptor, were at least 4-fold lower in extrastriatal subcortical regions than in striatal regions (average NAc BPND:amygdala BPND ratio). Cortical ROI BPND's were lowest. Nevertheless, PET imaging of [18F]NMB detected robust extrastriatal specific D2R specific binding that was significantly greater than background measures of nonspecific binding in the cerebellar reference region. Pretreatment with large doses of unlabeled eticlopride, a D2-like antagonist, does not alter cerebellar uptake, supporting the conclusion that this is an appropriate reference region devoid of specific saturable binding sites (Moerlein et al., 1997).

The magnitudes and rank order of the BPND's in striatal and extrastriatal regions detected by [18F]NMB are similar to those of raclopride (Fujimura et al, 2010; Ito et al., 1999). However, BPND's in these regions as detected by [18F]NMB are remarkably lower than those detected by [11C] FLB 457 (Esmaeilzadeh et al., 2010; Kodaka et al., 2010; Olsson et al., 1999; Suhara et al., 1999; Vilkman et al., 2000) and [18F]fallypride (Christian et al., 2000; Kegeles et al., 2010; Mukherjee et al., 2002), although the regional rank order of BPND's are roughly the same. It is difficult to accurately compare the magnitude of extrastriatal binding relative to striatal binding in this study with those reported for other high-affinity ligands due to differences in methods and regions selected for analysis. However, the average putamen:thalamus BPND ratio for [18F]NMB observed here, 8.55, seems to be in range of those reported for raclopride (Fujimura et al, 2010; Ito et al., 1999) and fallypride (Christian et al., 2000; Kegeles et al., 2010; Mukherjee et al., 2002; Slifstein et al., 2004). Given the high affinities of both [11C] FLB 457 (0.02 nM, Halldin et al., 1995) and [18F]fallypride (0.03 nM, Mukherjee et al., 1995) for binding to D2 and D3Rs, the lower BPND's as measured by [18F]NMB likely represent its relatively lower affinity for D2R (0.58 nM, Karimi et al., 2011) as well as selectivity for D2R subtype specific binding, minimizing the additional contribution from D3 receptor subtype specific binding sites that confound other less specific D2 radioligands (Karimi et al., 2011). [11C]raclopride specificity does not distinguish D2R from D3R but its total specific binding may be lower due to relatively lower affinity for D2R (1.3 – 2.5 nM, Elsinga et al., 2006) for D2R. Differences in nonspecific binding among radioligands may also contribute to differences in BPND's. Importantly, unlike these other radioligands, NMB D2R specific binding measurements are not confounded by endogenous levels of dopamine (Moerlein et al., 1997).

Striatal D2R BPND's estimated by [18F]NMB strongly negatively correlate with age, which extends findings using radioligands that do not differentiate D2R from D3R such as [11C]raclopride (Antonini and Leenders, 1993; Antonini et al., 1993; Ishibashi et al., 2009; Kim et al., 2011; Rinne et al., 1993; Volkow et al., 1996; Wang et al., 1996) and [11C]FLB 457 (Inoue et al., 2001; Kaasinen et al., 2000b; Kaasinen et al., 2002). This age-related finding with [18F]NMB also indicates that this radioligand can measure biologically relevant patterns in D2R binding. We did not find significant correlations between age and D2R BPND's in extrastriatal regions. However, age-related decreases in D2/D3Rs have been found in thalamus and insula with [11C]raclopride (Wang et al., 1996) and [11C]FLB 457 (Inoue et al., 2001; Kaasinen et al., 2000b; Kaasinen et al., 2002) as well as in hippocampus, amygdala, and frontal and temporal cortices with [11C]FLB 457 (Inoue et al., 2001; Kaasinen et al., 2000b). The relatively small sample size of our study limits our statistical power to identify a correlation between extrastriatal BPND's of [18F]NMB and age.

Importantly, our quantitative comparison of BPND as calculated by the three-compartment tracer kinetic method, graphical method with arterial input and graphical method with cerebellum as a reference region indicates that the last method is a valid and appropriate way to estimate extrastriatal BPND's. BPND estimates were reasonably similar across all three methods, although the tracer kinetic method tended to yield higher extrastriatal BPND estimates than the graphical methods. This finding extends those of the previous study of BPND estimates in striatum (Antenor-Dorsey et al., 2008). All three methods yielded BPND estimates that were highly correlated with each other within each extrastriatal ROI examined. Cortical BPND estimates derived from the primary analysis of 14 subjects (Figure 4C) were greater than those calculated from the secondary analysis of 8 unique subjects (Table 1) using the Logan graphical method with cerebellum as a reference region. This difference is most likely due to small sample sizes and the variability inherent in detection of low D2R levels in cortical regions.

This study has a number of strengths. First, it employs complementary tracer kinetic methods and peak and quantitative BPND analyses to identify regional differences in [18F]NMB activity and binding. This dual approach allows for confirmation of region-specific results and permits a regionally comprehensive investigation of D2R binding. Extrastriatal BPND values measured with this radioligand are low for subcortical and very low for cortical ROIs compared to those measured with [18F]fallypride and [11C]FLB 457 but this may be explained by the greater specificity of [18F]NMB for D2R than these other radioligands. Our techniques yielded relatively low variability for BPND measures, and resistance to competition from endogenous dopamine may partly account for this low variability. Preliminary power analyses based on our BPND data, in subjects whose ages cover a wide range, indicate that, to detect a 15% difference in D2R BPND's between groups with [18F]NMB in thalamus and amygdala, 20-27 subjects per group would be required. On the other hand, in cortical regions, large differences in D2R density between groups may be required for [18F]NMB to detect significant alterations. For example, based on our frontal cortical BPND data, it can be estimated that group sizes of 139-176 and 51-64 would be required to detect 30 and 50% differences between groups, respectively. The sensitivity of [18F]NMB in detecting changes in extrastriatal regions may be greater in groups with narrower age distributions. Overall, our results indicate that [18F]NMB may be quite useful in detecting differences in D2R in at least some extrastriatal regions between normal and disease states using moderate sample sizes.

One important limitation of this study is that there were some discrepancies between our regional distributions identified with the peak analysis compared to the a priori ROIs. The peak analysis did not detect peak [18F]NMB activity in nucleus accumbens, amygdala and hypothalamus as anatomically defined by the Talairach atlas (Talairach and Tournoux, 1988). These discrepancies are most likely due to the small size of these regions compared to the spatial resolution of the PET, loss of anatomical precision in the transformation to Talairach space, the contiguity with putamen in the case of the nucleus accumbens, and the relatively small number of subjects In addition, a potential weakness of PET imaging with [18F]NMB is that, due to the radioligand's high selectivity for D2R over D3R, BPND estimates in cortical regions may be too low and variable to accurately detect differences between groups but this of course will depend upon the potential magnitude of differences that might exist between groups. This issue requires further investigation. Although the observed BPND estimate for insula appears to be reasonably high, partial volume effects due to this region's proximity to putamen may have contributed. Finally, in clinical populations such as those with movement disorders,the 2 hour length of the scan reported here may be difficult to carry out. However, in this laboratory adults with Tourette syndrome or dystonia have been able to complete these scans.

In summary, PET imaging with [18F]NMB can quantify D2R subtype specific binding in extrastriatal as well as striatal regions. Importantly, the radioligand binds with high selectivity for D2R and thus can be used to obtain accurate PET measurements of D2R that are not confounded by D3R binding or receptor competition with endogenously-released dopamine. The utility of using [18F]NMB as a PET tracer to specifically identify changes in D2R within extrastriatal as well as striatal tissues in normal and diseased subjects should be examined further, given the importance of D2R in movement and psychiatric disorders.

Supplementary Material

Supp Fig S1 & Table S1

Acknowledgments

This study was supported by the NIH (5 T32 DA 007261-20, R01DK085575, 5 K24 MH087913-02, R01NS031001, R01NS058714, R01NS41509, R01NS075321, P30 NS048056), American Parkinson Disease Association (APDA), the Greater St. Louis Chapter of the APDA, the Barnes Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund), the Murphy Fund and the Tourette Syndrome Association.

Footnotes

The authors report no conflicts of interest.

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Supp Fig S1 & Table S1
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