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Published in final edited form as: Neuroimage. 2010 Apr 18;52(4):1505–1513. doi: 10.1016/j.neuroimage.2010.04.034

Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR

Dean F Wong X,+, Hiroto Kuwabara X, Andrew Horti X, Vanessa Raymont X, James Brasic X, Maria Guevara X, Weiguo Ye X, Robert Dannals X, Hayden Ravert X, Ayon Nandi X, Arman Rahmim X, Jeffery E Ming ++, Igor Grachev ++,*, Christine Roy ++, Nicola Cascella o
PMCID: PMC6580862  NIHMSID: NIHMS199581  PMID: 20406692

Abstract

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [11C]OMAR (JHU 75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [11C]OMAR. The CB1 binding (expressed as the distribution volume; VT) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [11C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the students t-test. When we ran a regression of the control subjects VT values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores, but there was a significant correlation between VT and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.49), (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [11C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In additon, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

Introduction

Cannabis sativa, that is known as marijuana has been used by people as a drug of abuse and medication throughout history.(Mechoulam, 1986) Δ9-Tetrahydrocannabinol (Δ9-THC), the principal component of marijuana, is known to activate cannabinoid receptors. (Pertwee, 2008) The cannabinoid receptors belong to GPCR-superfamily and currently two subtypes of cannabinoid receptors have been identified (Howlett et al., 2002): CB1-subtype that is primarily found in brain and neuronal tissue and CB2-subtype that is mainly found in immune tissue and, in lower concentration, in normal nervous tissue (Onaivi et al., 2008). Central CB1 receptors are involved in various brain functions and disorders including schizophrenia1 and depression, drug addiction and alcoholism (Mouslech and Valla, 2009). Even though the chemistry and pharmacology research of cannabinoids has reached enormous proportions(Hanus, 2009) the exact role of cannabinoid receptors in normal state and disease remains elusive.

Multiple lines of evidence show that cannabis and CB1 receptors play a role in psychotic illness and particularly in SZ (Andreasson et al., 1987; Arseneault et al., 2002; Chavarria-Siles et al., 2008; D'Souza, 2007; D'Souza et al., 2005; D′Souza et al., 2009; Giuffrida et al., 2004; Henquet et al., 2005; Leweke et al., 1999; Ujike et al., 2002; van Os et al., 2002; Zammit et al., 2002).

Studies with post-mortem brain in patients with SZ have showed a 25% increase of the binding of [3H]CP55,940, a non-subtype selective CB1/CB2 agonist, in the superficial layers of the posterior cingulate cortex (Newell et al., 2006) and a 64% increase of the binding of CB1 selective cannabinoid antagonist [3H]SR141716A in the anterior cingulate cortex (Zavitsanou et al., 2004). Dean and collaborators (Dean et al., 2001) found increased binding of a cannabinoid agonist [3H]CP55,940 in the dorsolateral prefrontal cortex (DLPFC) in SZ patients (independent of cannabis use prior to their death), while the increased numbers in the caudate-putamen was thought to be the result of cannabis use. In this study no change was observed in the hippocampus compared to normal controls. In contrast to these radiotracer in vitro binding studies, reduced cortical CB1 receptor messenger RNA and protein expression have been found post-mortem in DLPFC of subjects with SZ (Eggan et al., 2008), while another immunohistochemical study (Koethe et al., 2007) showed no alteration of density of CB1 receptor immunopositive cells in the brains of subjects with SZ. A more recent study demonstrated that immunodensity of CB1 receptors in the frontal cortex was significantly decreased (71±7%) in antipsychotic-treated subjects with schizophrenia but not in drug-free subjects (104±13%) (Uriguen et al., 2009).

The most advanced technique for studying central receptors in the living human and animal brain is PET. Until recently the quantitative PET imaging of CB1 receptors has been hampered by the lack of suitable radioligands. PET imaging of CB1 receptors will help to study the role of the CB1 in many CNS diseases, including schizophrenia. Better understanding of the fundamental mechanisms of the cannabinoid receptor system could direct the development of medications to treat these disorders. A preliminary PET study of CB1 in a subject with schizophrenia with [124I]AM281 suggested a feasibility of such investigation, but a poor signal-to-noise ratio of the radioligand was an obstacle for a further research including comparison of CB1 receptors in normal controls and subjects with SZ (Berding et al., 2006).

During the last two years, advances in medicinal radiochemistry have led to the development of radiolabeled CB1 PET probes with better imaging characteristics than those of [124I]AM281. Quantitative PET of the CB1 receptor has now become possible (Burns et al., 2007; Horti et al., 2006; Terry et al., 2009; Van Laere et al., 2009; Van Laere et al., 2008b; Yasuno et al., 2008) and studies with several classes of new CB1 radiotracers are in progress (see for review (Horti and Van Laere, 2008)). Our new radioligand, [11C]OMAR ([11C]JHU75528 (Fan et al., 2006)), exhibited good results for quantification of CB1 receptors in the mouse and baboon brain (Horti et al., 2006) and control human subjects (Horti et al., 2007; Wong et al., 2008b). In this report we are presenting the results of PET imaging of CB1 receptors with [11C]OMAR in healthy human controls and patients affected by SZ (Wong et al., 2008a), which demonstrate the utility of [11C]OMAR to image CB1 receptors.

Materials and Methods

Radioligand for human studies

[11C]OMAR ([11C]JHU75528) is a CB1 selective PET radioligand (Fan et al., 2006) was synthesized here for human studies via the previously published procedure (Horti et al., 2006) under the cGMP guideline (2005). The radioligand was synthesized in high radiochemical purity (>99%) and specific radioactivity (266±78 GBq/μmol, n=16). The precursor for the radiosynthesis was purchased from IsoSciences (King of Prussia, PA). Toxicology and radiation dosimetry studies were carried out and demonstrated safety and tolerability. These safety and toxicology studies were consistent with local IRB approval (see Appendix Description 1).

Study Design

To examine the distribution of CB1 receptors in the human brain, in both healthy controls and patients affected by SZ, we conducted a single-center PET study. In this study control human subjects were initially compared with a single cohort of 10 subjects with SZ.

Study participants

Healthy adult control subjects were recruited via advertisements in local newspapers, word of mouth, and announcements at local universities. Adult subjects with SZ were recruited from the outpatient clinic of the Department of Psychiatry at Johns Hopkins Hospital.

All subjects received thorough medical and psychiatric screenings, which specifically examined current and earlier medications. All control subjects were free of neuroleptic, cannabinoid, serotonergic, and dopaminergic drugs at the time of PET scanning, and had been treatment-free for a period of at least 6 months before the start of the study.

Study procedures were conducted in accordance with the Declaration of Helsinki Principle of 2004. The Institutional Review Board of The Johns Hopkins University School of Medicine approved the studies and the informed consent documents. All participants gave their written informed consent.

The control cohort consisted of ten healthy males, with a mean age of 33± 11 years, ranging from ages 21-51 and comprised 8 African-Americans, 1 Asian and 1 Caucasian. The SZ cohort consisted of 9 males and 1 female, with a mean age of 42 ± 9 years, ranging from ages 30-54 and comprise 7 African-Americans, 1 Indian and 2 Caucasians. (see Appendix Table 1, 2)

Inclusion criteria for the controls included: BMI between 18 and 28 kg/m2, smoking consumption of less than 5 cigarettes a day and also the ability to stop smoking while participating in the study, and finally; all controls had to be deemed to be healthy by a detailed medical history and complete physical examination. Potential subjects were also excluded if there had a history or presence of drug or alcohol abuse (alcohol consumption > 40 grams/day).

The subjects with schizophrenia all had a DSM-IV-TR (Disorders, 2000) diagnosis of schizophrenia, and were treated with olanazapine or risperidone monotherapy for at least 2 months prior to screening. They did not differ significantly in terms of duration of illness.

We excluded any of the schizophrenia subjects if they had a 1) BPRS hallucinatory behavior, unusual thought content, suspiciousness or conceptual disorganization item scores > 4 (moderately severe) on any single item; 2) CDSS total score > 10 (depression) or a score of > 0 on item 8 (suicidality); 3) SAS score > 0.6 (6 total); and 4) Barnes Akathisia Scale global score > 3.

Study Procedures

Dynamic PET scans of 90 minutes followed a slow-bolus injection of [11C]OMAR (mean total dose = 703 MBq; specific radioactivity = 222 - 296 GBq/μmole).

All PET scans were carried out on the second-generation High-Resolution Research Tomograph (ECAT HRRT); CPS Innovations, Inc.), an LSO-based, 2.5mm-resolution, dedicated brain PET scanner (Sossi et al., 2005).

For co-registration with the PET data to enhance anatomical definitions, each participant received a volumetric MRI scan acquired using a spoiled GRASS (gradient recalled acquisition in steady state) (SPGR) sequence on a GE 1.5T Signa Camera (GE Healthcare, Chalfont St Giles, UK).

PET Scan Procedures

An intravenous catheter was inserted to the antecubital vein for ligand injection and an arterial catheter was inserted in the radial artery at wrist on the other hand to obtain blood samples. A thermoplastic mask was custom-made for each subject to reduce head motion during the scan. At 15 minutes before ligand injection, the subject was positioned in the scanner. A 6-min attenuation scan was performed using a rotating Cs-137 point source. The 90-min emission scan started with a slow bolus injection (over one minute) of radioligand about 20 mCi (range; 19.53 to 20.43 mCi) in a 3-D list mode. Small amounts of arterial blood (∼2ml) were sampled every 5 seconds initially and at prolonging intervals toward the end of the scan. Radioactivity in plasma samples were measured with a gamma counter and corrected for physical decay to the injection time. Large amounts of arterial blood (∼5 ml) were sampled at 0, 5, 10, 30, 60 and 90 min for determination of [11C]OMAR and its radioactive metabolites in plasma as described elsewhere (Hilton et al., 2000; Horti et al., 2006).

Reconstruction of emission scan

PET images were reconstructed using the iterative ordered-subset expectation-maximization (OSEM) algorithm correcting for attenuation, normalization, scatter, randoms and dead-time (Jones et al., 2006; Rahmim et al., 2005). The following frame schedule was used: Four 15-sec, four 30-sec, three 1-min, two 2-min, five 4-min, and twelve 5-min frames, or a total of 30 frames for the 90 min scan. The radioactivity was corrected for physical decay to the injection time. Each PET frame consisted of 256 (left-to-right) by 256 (nasion-to-inion) by 207 (neck-to-cranium) voxels.

Data analysis

Volumes of Interest

VOIs were generated by spatially normalizing (Ashburner and Friston, 2007a) a standard VOI template(Tzourio-Mazoyer et al., 2002) to each individual subject's MRI and was then edited manually for errors associated with spatial normalization. The cingulate cortex VOI, the region of particular interest, was divided into anterior, middle, and posterior cingulate VOIs by the anterior and posterior commissure planes (Plane A and B). The U-shaped anterior cingulate VOI was further divided into dorsal, rostral, and sub-callosal subdivisions by a coronal plane that passed through the anterior tip of corpus callosum (Plane C) (Bush et al., 2000; Fornito et al., 2006; Fornito et al., 2008; Vogt et al., 2003; Vogt and Laureys, 2005). The classification process was performed in the Talairach-oriented MRI space (i.e., anterior and posterior commissure pointes were on the Y axis, and mid-sagittal plane was one the YZ plane) (Talairach and Tornoux, 1988). Finally, the VOIs were transferred to PET space using MRI-to-PET coregistration parameters(Ashburner and Friston, 2007b) and applied to individual PET frames to obtain TAC.

Radioactive Plasma and Radiolabeled Metabolite Data

The radioactive metabolites in blood were analyzed by HPLC under the same conditions that we used previously in baboon [11C]OMAR studies (Horti et al., 2006). The HPLC analysis demonstrated no substantial difference between radioactive metabolites in the baboon and human blood (data are not presented). The average parent ligand in plasma was 41% at 60 minutes by HPLC. The radioactive metabolites were assumed not to enter the brain because of weak lipophilicity, as has been shown in our previous rodent and baboon studies (Horti et al., 2006). The time profiles of total metabolites were fitted by a sum of exponential functions (zero derivative at time 0) to separate the total radioactivity into [11C]OMAR and metabolites. Metabolite-corrected plasma TAC were used in the model parameter estimation, with the exception of the total plasma TAC, which was used for the calculation of the radioactivity in the tissue vasculature when applicable.

Derivation of outcome variables

The distribution of volume of [11C] OMAR VT was obtained for each region by plasma reference graphical analysis (PRGA (Logan et al., 1990)). In a preliminary study, PRGA showed more robust estimates of VT than the two-compartment model, as measured with time-dependency (i.e., PET frames used for data analysis) of estimates and the magnitude of inter-subject variability. Because of the lack of a reliable reference region for [11C]OMAR (See Discussion), we concluded that the BPND (Innis et al., 2007) is not appropriate for quantification of this radioligand.

Head motion correction

Head motions during the emission scan were not corrected in this analysis because apparent head motions were not detected on visual inspections of TACs in each subject. In addition, VT estimates without and with head motion correction (HMC) were essentially identical for PRGA (VT [HMC] = 1.01·VT [noHMC] - 0.004; R2 = 0.989).

Behavioral analysis

We carried out a correlational analysis of these summary categories and the regional VT. We particularly focused on the summary categories of psychotic and withdrawal symptoms, as these are representative of the most prominent symptoms in SZ.

Results and Discussion

Based on safety and tolerability studies (see Appendix Description 1), we elected to inject a mass approximately 0.14 μg/kg during each radiotracer injection. The radiation dosimetry estimates in mice provided an effective dose of 10 – 20 mCi (370 – 740 MBq). There were no significant adverse experiences reported during the studies, in either the healthy control subjects of subjects with SZ.

Outcome variable of the [11C]OMAR human studies

The pons showed the lowest accumulation of the radioactivity among brain regions. However, inter-subject variations (as measured by standard deviation across subjects) increased from a 10% range for VT to a 20% range for BP when the pons was used as a reference region. Therefore, it is likely that VT estimates within the pons maybe uncertain because of its relatively small size (∼10 ml) compared to typical reference regions (e.g., ∼90 ml for cerebellum, ∼50 ml for occipital cortex) as well as the low counts in this region. In addition, it has been noted that one of the highest reductions in VT occurred in the pons in the monkey brain as measured with [11C]MePPEP, a separate CB1 receptor ligand, after pretreatment with Rimonabant (3.0 mg/kg i.v.). Other researchers (Burns et al., 2007; Yasuno et al., 2008) have suggested that white matter (centrum semiovale) may be used as a reference region for [18F]MK-9470, another CB1 receptor radioligand. However, in our study, white matter TAC continued to increase for the 90 min period for [11C]OMAR even when white matter VOIs were limited to voxels that were less affected by the partial volume effect (i.e., pure white matter voxels). Thus, we suggest that [11C]OMAR showed different kinetics in cerebellum than cortical regions and/or partial volume effects may not be completely eliminated even for HRRT. For all the above reasons, we concluded that pons and white matter may not be used as a reference region for calculation of BPND, and that BPND may not be accessible for [11C]OMAR. Therefore, we used VT as the main outcome variable instead of BPND.

[11C]OMAR binding and brain regional distribution in control subjects

The brain time-activity curves of [11C]OMAR peaked at approximately 20 minutes post injection (% SUV ranged from 136 to 207% in the putamen) and decreased gradually thereafter to reach a SUV between 80 and 117% at 90 min. (Figure 1). In all 10 control subjects the VT values ranged from 0.79 to 1.82 across multiple cortical and subcortical regions. Because of the high resolution of the HRRT PET scanner we were able to assess relatively small regions including the globus pallidus and subdivisions of cingulate cortex.

Figure 1.

Figure 1

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Time (radio-)activity curves (TACs) of selected brain regions shown as mean standard uptake values (SUV; g/ml) across 10 healthy subjects.

Within the controls, the globus pallidus showed the highest VT, with a mean of 1.47 +/- 0.25 (SD), with a range of 0.95 to 1.82 in individual subjects (Figure 2,3). The cingulate cortex (mean 1.23 +/- 0.16(SD), range of 1.01 – 1.49) and the putamen (mean 1.32 +/- 0.20(SD), range of 1.05 – 1.63) also showed high binding. The intermediate uptake was in the hippocampus, cerebellum and cortex. The lowest accumulation of the [11C]OMAR radioactivity was seen in white matter, the pons and thalamus. It is noteworthy that the previous autoradiography study with cannabinoid agonist [3H]CP55,940 (Glass et al., 1997; Herkenham et al., 1990) demonstrated the highest binding in the hippocampus and frontal cortex and intermediate binding in the globus pallidus and putamen, whereas [11C]OMAR manifests highest accumulation of radioactivity in the basal ganglia, including the globus pallidus and putamen (Figures 3). However, the in vivo regional distribution of [11C]OMAR in the human brain (Figure 4) is consistent with the PET human data from other CB1 selective PET radioligands including [18F]MK-9470 (Burns et al., 2007; Van Laere et al., 2008a), [11C]MePPEP (Terry et al., 2009) and [124I]AM281 (Berding et al., 2006). The differences between in vivo and in vitro CB1 binding have been discussed by other researchers (Burns et al., 2007; Van Laere et al., 2008a) who concluded that there could be a number of reasons for the differences, including a limited availability of the hippocampus CB1 receptors for in vivo binding given this ∼85% of these receptors are located in intracellular vesicles (Burns et al., 2007; Coutts et al., 2001).

Figure 2.

Figure 2

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Trans-axial images of distribution volume (VT) of [11C}OMAR, mean of 10 healthy subjects in a standard space (left panel), a standard MRI (right), and merged image (middle). Volumes of interest of selected structures in the standard space are shown on the VT image and MRI. Regions are insula (I), putamen (P), glubus pallidus (G), thalamus (T), and caudate nucleus (C).

Figure 3.

Figure 3

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Brain regional total volume of distributions (mean VT ± SD, n=10) in the control cohort in the PET studies with [11C]OMAR.

Figure 4.

Figure 4

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Correlation of PET regional volumes of distribution of [11C]OMAR in controls(VT, mean ± SD, n=10) with post-mortem autoradiographic CB1 density of binding [3H]CP55,940 in the adult human brain (Bmax). The regional Bmax values were calculated here as means of all sub-regions that are presented in the autoradiography paper (Glass et al., 1997).

Effect of aging on the [11C] OMAR binding in controls and subjects with schizophrenia

We also correlated the [11C]OMAR regional volume of distribution (VT) with age. Within the control group we found a significant age-associated decline of [11C]OMAR VT in the globus pallidus (r = -0.66, p < 0.05), the region with the highest uptake of [11C] OMAR. Other regions of intermediate to high [11C] OMAR uptake, such as the putamen and cortex also showed a decline with age, but this trend was not statistically significant. This supports results from previous studies that found no significant trend of the CB1 radioligand [18F]MK-9470 uptake in the hippocampus formation with aging within a group of normal male controls (range = 18-70 year old) (Van Laere et al., 2008a), although an age related increase of [18F]MK-9470 uptake in the entorhinal cortex/amygdala was observed in female controls.

Within the cohort with SZ, there was no significant association with age in any region. Furthermore, when the patients with SZ were plotted against the regression of the controls with age, at least one to several of the schizophrenia data points fell outside of the 95% prediction interval of the regression line. This was the case in the globus pallidus, where we saw a significant decline with age in controls, as well as in all other regions. Figure 5 shows the regression with age in several regions, including globus pallidus.

Figure 5.

Figure 5

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Effect of aging on the binding of [11C]OMAR (VT) in the various brain regions. Among the controls only, regression analysis of[11C]OMAR VT with aging was done (solid black lines, dotted lines indicated 95% prediction interval). Data from subjects with schizophrenia was then plotted against this regression (red triangles).

These PET results are consistent with an autoradiography study that demonstrated a substantially larger binding of [3H]CP55,940 in the basal ganglia of the neonatal brain (BmaxPutamen=86 fmol/mg, BmaxGlobus pallidus=118 fmol/mg) versus the human adult brain (BmaxPutamen=44 fmol/mg, BmaxGlobus pallidus=82 fmol/mg) (Glass et al., 1997), but the PET data contradict to another [3H]CP55,940 autoradiography study that found that the CB1 binding in a gender-mixed set of human brains increases progressively from fetus and early prenatal stages to adulthood(Mato et al., 2003). We are not aware of the post-mortem CB1 binding studies within the aging human brain.

[11C]OMAR PET imaging of subjects with schizophrenia

A comparison of [11C]OMAR binding in the control subjects and subjects with SZ demonstrated a higher VT values in all brain regions of subjects with SZ (Figure 6), and this increase was significant in the pons by t-test (p < 0.05). The data did contain one outlier with extremely low CB1 binding (potentially a plasma input function problem), but all other psychological and demographic variables were within the group means. There was indeed an increase (15-22%) in binding in the most brain regions of the subjects with SZ, compared to controls, but the difference was not significant. However, in the pons the increase (23%) of VT in subjects with SZ compared to controls was significant (SZ VT GP = 0.93 ± 0.27; controls VTGP = 0.72 ± 0.07). Previous autoradiography data in schizophrenia demonstrated an increase of the [3H]SR141716 binding in the anterior cingulate cortex (Zavitsanou et al., 2004) and [3H]CP55,940 binding in the posterior cingulate cortex (Newell et al., 2006). We measured the VT values of [11C]OMAR in sub-regions of the cingulate cortex of SZ and control subjects (Figure 7), and found a non-significant increase of [11C]OMAR binding in all subdivisions of the cingulate cortex in subjects with SZ.

Figure 6.

Figure 6

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Regional total volume of distributions (mean VT ± SEM) of [11C]OMAR are greater in SZ subjects than in controls. VT was signficantly higher in SZ in the Pons (PO), p < 0.05.

Figure 7.

Figure 7

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Correlation of [11C]OMAR VT in the brain regions versus BPRS withdrawal scores (SZ group).

In order to examine even more rigorous subject matching, we used a t-test to compare the VT values of [11C]OMAR in the two SZ and control subjects matched by age, educational level and also parental SES, and found a significantly higher mean value for some regions such as the occipital cortex (mean VT=1.21(sd=0.05) c.f. mean VT=0.92(sd=0.05); p=0.029) and the putamen (mean VT=1.42(sd=0.06) c.f. mean VT=1.08(sd=0.04); p=0.015). However, as this subsample contained only a very small number of subjects, these findings are supportive but must be replicated. We would suggest that future studies should consider utilizing matching criteria that include racial group and educational level (Dickinson et al., 2007; Resnick, 1992) in larger samples.

All patients with SZ that we studied were taking the antipsychotic drugs olanzapine or risperidone, so there is a chance that these drugs may have affected the CB1 binding, as there have been a number of recent reports on this matter. Thus, it was found that risperidone treatment increased CB1 binding in the rat caudate nucleus, hippocampus and amygdala (Secher et al., 2009). In addition, ex vivo experiments in Sprague rats have demonstrated that olanzapine significantly decreases CB1 binding in the dorsal vagal complex of the brainstem in rats (Weston-Green et al., 2008). However, no evidence of binding of antipsychotic drugs clozapine, olanzapine and haloperidol at CB1 receptor was found in vitro (Theisen et al., 2007). Other antipsychotic drugs such as aripriprazole and haloperidol have been shown to have little effect on the CB1 binding ex vivo (Weston-Green et al., 2008). Experiments with rats that were chronically treated with various antipsychotic drugs demonstrated (Sundram et al., 2005) that clozapine decreases CB1 binding ([3H]CP55,940) in the nucleus accumbens while other regions (cortex, hippocampus and striatum) showed no change. However, the same study (Sundram et al., 2005) showed no effect with haloperidol, chlorpromazine or olanzapine. Overall, the existing body of research suggests that most antipsychotic drugs do not bind with CB1 receptor in vitro and do not change the CB1 radiotracer binding in the cortex and striatum (the regions with highest density of the CB1 receptor), but may decrease the CB1 radiotracer binding in the brainstem and amygdala, or, in case of risperidone, may increase the CB1 binding in the hypothalamus, hippocampus and amygdala. Risperidone and olanzapine seem to show the opposite effect on the CB1 binding of radiotracers in rodents. Because all of the SZ patients were prescribed olanzapine or riperidone we compared the [11C]OMAR binding in both subgroups, but found no significant difference (Appendix Figure 1).

[11C]OMAR PET binding and relationship of behavioral sub scores (BPRS for subjects with schizophrenia

The elevated binding of [11C]OMAR in subjects with SZ (Figure 6, 7) suggests that CB1 binding might correlate with type and severity of clinical symptoms of schizophrenia. However, we found no correlation between total score on the brief psychiatric rating scale (BPRS) and [11C]OMAR VT. In addition, there was no obvious association between the VT values and BPRS subscores, although there was a trend for the BPRS withdrawal symptom scores, whose severity showed a trend level with a decline of VT in the cortical brain regions (Figure 7). However, when we examined the difference and ratio between BPRS sub scores for positive symptoms (psychosis-type symptoms) to negative symptoms (withdrawal-type symptoms), we found some significant results. The SZ subjects (when examining 9 of the patients with SZ, excluding the outlier mentioned above) with the highest psychosis to withdrawal scores ratio, had the highest elevated CB1 receptors, suggesting a possible interaction between positive and negative symptoms and CB1 receptors (Figure 8). We found a significant correlation between the psychosis to withdrawal scores ratio and VT values in a number of different brain regions, including the frontal lobe (r = 0.49, p = 0.05), and the middle and posterior cingulate (r=0.71 p = 0.03, and r=0.79, p = 0.004 respectively). These results suggest that CB1 receptor binding in the subjects with SZ increases with severity of the positive symptoms and decreases with severity of negative symptoms.

Figure 8.

Figure 8

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Correlation of [11C]OMAR VT in the brain regions of SZ subjects and severity of symptoms: VT vs. Positive/Negative symptoms.

Conclusions

[11C]OMAR readily enters human brain and shows a regional brain distribution that is consistent with that of cannabinoid receptors subtype 1 (CB1). The imaging properties of [11C]OMAR are sufficient for studying CB1 receptors in the human brain, including in those with neuropsychiatric disorders such as schizophrenia. It has reversible kinetics during the 90 minute PET scan. There were no significant safety issues with [11C] OMAR at high specific activity.

The total volume of distribution VT values of [11C]OMAR in the male control subjects show little age dependence in most brain regions, with low to intermediate binding that is consistent with the observations of other researchers that have utilized the CB1 tracer [18F]MK-9470. However, [11C]OMAR binding does appear to decline with increasing age in the healthy controls in the globus pallidus and putamen, the regions with highest values of VT.

Having demonstrated the feasibility and safety of [11C] OMAR in humans, our initial studies applied to a patient group, demonstrated elevated VT values in a small cohort of subjects with schizophrenia compared to normal controls. This VT difference was significant in the globus pallidus when examining all controls vs. all patients and also when the subjects with SZ were compared with age-matched controls. The age-matched cohort was a small group of 6 controls and 6 patients. Lastly, there were significant differences in the occipital lobe and putamen when additional matching criteria including racial group and education level were incorporated. Within patients with SZ, the VT values in certain brain regions correlated with positive and inversely with negative symptoms, suggesting that it may be possible to characterize the CB1 VT as it relates to type and severity of clinical symptoms in SZ. It may well be that accounting for the negative, as well as the positive symptoms of the disorder may help our further understanding of the role of the CB1 cannabinoid receptors in SZ. We recognize the ratio and differences of BPRS subscores has not been widely cited, and that this study involved a small sample. However this preliminary finding suggests a potential relationship between behavioral characteristics and CB1 binding, and is provocative. If supported with large numbers could provide neurochemical clues to CB1 involvement in schizophrenia. It is possible that subjects with SZ who have an inherent tendency to a particular symptomatology have abnormal VT values. It may be even possible that VT values may help predict those that are at greater risk of early decline into the negative syndrome of SZ, and thus these important initial findings warrant greater investigation.

Supplementary Material

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Acknowledgments

Sanofi-Aventis, NIH grants DA000412, MH079017, Dean F. Wong

Footnotes

1

SZ=schizophrenia; PET=positron-emission tomography; BMI=Body mass index; BPRS=Brief Psychiatric Rating Scale; CDSS=Calgary Depression Scale for Schizophrenia; SAS=Simpson Angus Scale; MRI=magnetic resonace imaging; VOI=volume of interest; TAC=time-activity curves; BPND=binding potential; VT=total distribution volume; CB1= Cannabinoid receptor type 1; Fr=frontal cortex, Tp=temporal cortex, Pa=parietal cortex, Oc=occipital cortex, Fs=fusiform gyrus, Cg=cingulate cortex, PH=parahippocampus, Hp=hippocamus, In=insula, Pu=putamen, CN=caudate nucleus, GP=globus pallidus, Th=thalamus, Cb=cerebellum; vAC=ventral anterior cingulate, aAC=anterior anterior cingulate, dAC=dorsal anterior cingulate, mCg=middle cingulate, pCg=posteriorcingulate

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