[Show abstract][Hide abstract] ABSTRACT: In Alzheimer's disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.
PLoS ONE 06/2015; 10(6):e0129618. DOI:10.1371/journal.pone.0129618 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Disrupted-in-schizophrenia-1 (DISC1) is a promising genetic susceptibility factor for major psychiatric conditions, such as schizophrenia. We hypothesized that the mutant DISC1 alters the homeostasis of multi-receptor interactions between dopaminergic [dopamine 2/3 (D(2/3)R)], glutamatergic [metabotropic glutamate 5 (mGluR5)], cannabinoid 1 (CB(1)R), and nicotinic acetylcholine (α4β2-nAChR) receptors in the brains of mice with inducible forebrain neuronal expression of dominant-negative mutant DISC1.
The quantitative in vitro autoradiography was performed with positron emission tomography (PET) ligands using [(11)C]raclopride (D2/3R), [(11)C]ABP688 (mGluR5), [(11)C]OMAR (CB(1)R), and [(18)F]AZAN (nAChR). Total binding (pmol/cc) from standard and binding index, defined as [(region of interest - reference) / reference], was analyzed in the parasagittal sections. The cerebellum was used as a reference for D(2/3)R, mGluR5, and α4β2-nAChR, while the midbrain was the reference tissue for CB(1)R, because of the high density of CB(1)R in the cerebellum.
We observed a significant positive correlation between mGluR5 and D2/3R in the nucleus accumbens (NAc) in mutant DISC1 (rho = 0.6, p = 0.04; y = 0.02 x + 6.7) and a trend of negative correlation between those receptors in the dorsal striatum (DS) in control animals (rho = -0.5, p = 0.09; y = -0.03 x + 23), suggesting a co-release of dopamine (DA) and glutamate (Glu) in the NAc, but not in the DS. There were trends of an inverse relationship between striatal CB(1)R and D(2/3)R (rho = -0.7, p = 0.07) as well as between dorsal thalamic nAChR and striatal D2/3R (rho = -0.5, p = 0.08). There was no statistically significant difference of the individual receptor density in the majority of brain regions.
The mutant DISC1 altered the homeostasis of multi-receptor interactions of coincident signaling of DA and Glu in the NAc, but not in the DS, and mutually negative control of striatal CB(1)R and D2/3R. Multi-receptor mapping with PET ligands in relevant animal models could be a valuable translational approach for psychiatric drug development.
Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 10/2014; 17(3). DOI:10.1007/s11307-014-0786-4 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The 4-[(18) F]-fluorobenzyltriphenylphosphonium cation was synthesized by a series of microwave reactions from no carrier added [(18) F]-fluoride. The microwave procedure reduced the quantity of reagents used and synthesis time when compared with the original synthesis. In addition, problematic solid phase extraction, sodium borohydride reduction by column and inconsistent yields with excessive precipitate formation during the bromination step were eliminated. The 4-[(18) F]-fluorobenzyltriphenylphosphonium cation was produced radiochemically pure in 8.3% yield with a specific radioactivity of 534.5 ± 371.4 GBq/µmole at end of synthesis.
Journal of Labelled Compounds and Radiopharmaceuticals 10/2014; 57(12). DOI:10.1002/jlcr.3241 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: The huge thermogenic capacity of BAT is an attractive target for anti-obesity drugs. Yet, our knowledge of human BAT is very limited. Here, we show the unique value of FBnTP PET for elucidating the functional architecture of BAT. FBnTP is an inverse correlate of the core mechanism of BAT thermogenesis - the uncoupling protein-1. Thus, thermogenic uncoupling is expected to result in dose-dependent FBnTP washout.
Methods: FBnTP (9.5 to 10.5 mCI) was introduced IV in 9 healthy subjects, and dynamic PET was carried out at room temperature (RT) for 20 or 30 min. Then, mild cold stimulation (CS) was given, using cooling vest, for the remainder of the scan (60 or 90 min). In 4 of 9 subjects, FDG PET was carried out within a week after FBnTP PET.
Results: In 7/9 subjects, FBnTP showed rapid uptake and extensive accumulation in BAT at RT, with ratio to background > 6:1. Supraclavicular BAT demonstrated the most prominent FBnTP uptake; FBnTP BAT uptake was also observed in the neck and paravertebral areas. CS resulted in a rapid onset (minutes) of FBnTP washout from BAT. FBnTP-induced washout was observed in substantial, but not all, BAT areas. FBnTP decreased by 25-40% compared to baseline activity. The spatial distribution of FBnTP correlated well with paired FDG PET/CT (n =4). FBnTP-FDG scans allowed identifying BAT regions (1) responsive to cold stimulation (FBnTP washout - FDG positive), (2) unresponsive (FBnTP positive but no washout - FDG negative) and (3) regions that are thermogenic at RT (FBnTP negative - FDG positive).
Conclusions: FBnTP provides high-contrast PET images of BAT. FBnTP indicates that BAT is a highly responsive organ, but only partially activated by cold stimulation. FBnTP-FDG allowed dissecting the thermogenic components of BAT, and provided more accurate assessment of BAT volume than each one separately. FBnTP enables obtaining information critical for developing BAT anti-obesity drugs, and assessing their efficacy.
Research Support: NIH DK090780-01
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET).
We prepared the high-affinity (K(d) = 0.2 nM) α7 nAChR agonist, 5'-(2-[(18)F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [(18)F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [(18)F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates.
[(18)F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90 min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/μmol (3,781 mCi/μmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain.
Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET.
Nuclear Medicine and Biology 05/2013; 40(6). DOI:10.1016/j.nucmedbio.2013.04.005 · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To examine the association between regional brain uptake of a novel amyloid positron emission tomography (PET) tracer florbetapir F 18 ([(18)F]-AV-45) and cognitive performance in a pilot study.
Cross-sectional comparison of [(18)F]-AV-45 in AD patients versus controls.
Three specialty memory clinics.
Eleven participants with probable Alzheimer disease (AD) by NINDS/ADRDA criteria and 15 healthy comparison (HC) participants.
Participants underwent PET imaging following a 370 MBq (10 mCi) intravenous administration of [(18)F]-AV-45. Regional/cerebellar standardized uptake value ratios (SUVRs) were calculated. Cognition was assessed using Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Wechsler Logical Memory IA (immediate recall) test (LMIA), and verbal category fluency.
Greater [(18)F]-AV-45 SUVR was associated with poorer performance on all cognitive tests. In the HC group, occipital, parietal, precuneus, temporal, and cortical average SUVR was associated with greater ADAS-Cog, and greater anterior cingulate SUVR was associated with lower LMIA. Two HC participants had [(18)F]-AV-45 cortical/cerebellar SUVR greater than 1.5, one of whom had deficits in episodic recall and on follow-up met criteria for amnestic mild cognitive impairment.
[(18)F]-AV-45 SUVR in several brain regions was associated with worse global cognitive performance particularly in HC, suggesting its potential as a marker of preclinical AD.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 03/2013; 21(3):272-8. DOI:10.1016/j.jagp.2012.11.016 · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prior studies using positron emission tomography (PET) or single-photon emission computed tomography techniques have reported inconsistent findings regarding differences between patients with restless legs syndrome (RLS) and control patients in the striatal dopamine-2 receptor (D2R) binding potentials (BP). D2R-BP does reflect receptor-ligand interactions such as receptor affinity (K(d)) and density (β(max)) or neurotransmitter synaptic concentrations. Thus, differences in D2R-BP reflect changes in these primary factors. PET techniques are currently available to estimate D2R β(max) and K(d).
Separate morning and evening PET scans were performed. The D2R-BP were measured in basal ganglia using [(11)C]raclopride.
Academic medical center.
Thirty-one patients with primary RLS and 36 age- and sex-matched control patients completed the study.
Patients with RLS had lower D2R-BP in putamen and caudate but not the ventral striatum. A subgroups analysis of those RLS patients who had not previously taken dopaminergic medications continued to show a significantly lower D2R-BP in the posterior putamen. D2R-BP did not differ between night and day for either group. D2R β(max) and K(d) did not differ significantly between patients with RLS and control patients but did show a strong and significant increase at night in the ventral striatum. Primary and secondary clinical measures of disease status failed to show any relation to D2R in any brain region.
Given the lack of any difference in either β(max) or K(d) and the prior studies supporting an increase in presynaptic dopaminergic activity, the current changes found in D2R-BP likely reflect an increase in synaptic dopamine. CITATION: Earley CJ; Kuwabara H; Wong DF; Gamaldo C; Salas RE; Brašić JR; Ravert HT; Dannals RF; Allen RP. Increased synaptic dopamine in the putamen in restless legs syndrome. SLEEP 2013;36(1):51-57.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
α7-nicotinic acetylcholine receptor (α7-nAChR) is one of the major neuronal nAChR subtypes. α7-nAChR is involved in variety of neuronal processes and disorders including schizophrenia and Alzheimer's disease. A number of α7-nAChR PET radioligands have been developed, but a quality radiotracer remains to be discovered.
High binding affinity α7-nAChR ligands A-833834 and A-752274 were radiolabeled with (11)C. Baseline and blockade biodistribution studies in the mouse brain of [(11)C]A-833834 (5-(6-(5-[(11)C]methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-1H-indole) and [(11)C]A-752274 (2-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-7-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)-9H-fluoren-9-one) were performed. [(11)C]A-752274 was evaluated in a baseline baboon PET study.
[(11)C]A-833834 and [(11)C]A-752274 were synthesized by radiomethylation of corresponding des-methyl precursors. The radioligands were prepared with radiochemical yield of 12%-32%, high specific radioactivity (330-403GBq/μmol) and radiochemical purity>95%. Dissection studies with [(11)C]A-833834 demonstrated low specific α7-nAChR binding in the mouse brain. [(11)C]A-752274 specifically (~50%) labeled α7-nAChR in the mouse thalamus. However, [(11)CA-752274 exhibited low brain uptake in baboon (%SUV<100).
Two novel α7-nAChR ligands radioligands were synthesized and studied in animals. Specific binding of [(11)C]A-833834 in the mouse brain is low due to the insufficient binding affinity of the radioligand. The very high binding affinity [(11)C]A-752274 exhibited good specific binding in the α7-nAChR-rich mouse brain regions. The low uptake of [(11)C]A-752274 in the baboon brain is due to its high hydrophilicity, rapid metabolism or other properties. Future development of α7-nAChR PET radioligands will be based on compounds with high binding affinities and good blood-brain barrier permeability.
Nuclear Medicine and Biology 01/2013; 40(3). DOI:10.1016/j.nucmedbio.2012.11.013 · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: 18F-labeled p-fluorobenzyltriphenyl phosphonium (18F-FBnTP) is a member of a new class of positron-emitting lipophilic cations that targets the mitochondria in a membrane potential-dependent manner. The aim of this study was to assess the biodistribution and radiation dosimetry of 18F-FBnTP in healthy humans.
Methods: Three healthy subjects (1 male and 2 female; age, 26-29 y) were injected with 208 ± 14 MBq of 18F-FBnTP. During a 3-h period, each subject underwent 9 serial rapid 3D PET and 2 low-dose CT acquisitions on a PET/CT camera. PET/CT images were registered across time points. Source organ contours (19-20) drawn manually on a CT were overlaid onto registered PET images to extract time-activity curves. Time-integrated activity coefficients (TIACs) derived from time-activity curves using a combination of numerical and analytical method were given as input to OLINDA/EXM for dose calculations. Dynamic voiding-bladder model was used to obtain TIAC for urinary bladder contents by assuming a 3.5 h voiding interval.
Results: Increased uptake was observed in the liver, gallbladder, kidneys, adrenals and gastrointestinal tract source organs. The highest organ absorbed doses (µGy/MBq) were observed for the liver (128), urinary bladder wall (125), gallbladder wall (106) and kidneys (79). The mean effective dose based on ICRP 60 tissue weighting factors was 27 µSv/MBq. For a 370-MBq 18F-FBnTP, the effective dose is 10.0 mSv, and the absorbed dose to critical organ (liver) is 47.5 mGy.
Conclusions: The liver is the critical organ for 18F-FBnTP, in humans. A maximum, single administration of 389 MBq (10.5 mCi) of 18F-FBnTP can be safely administered without exceeding the Radioactive Drug Research Committee limits specified in 10 Code of Federal Regulations 21, part 361
[Show abstract][Hide abstract] ABSTRACT: The radiosynthesis and in vivo evaluation of 5-(5-(6-[(11)C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole [(11)C]rac-(1), a potential PET tracer for α7 nicotinic acetylcholine receptors (α7-nAChR), are described. Syntheses of the nonradioactive standard rac-1 and corresponding desmethyl precursor 7 were achieved in several reaction steps. Radiomethylation of 7 with [(11)C]CH(3)I afforded [(11)C]rac-1 in an average radiochemical yield of 30 ± 5% (n=5) with high radiochemical purity and an average specific radioactivity of 444 ± 74 GBq/μmol (n=5). The total synthesis time was 30 min from end-of-bombardment. Biodistribution studies in mice showed that [(11)C]rac-1 penetrates the blood-brain barrier and specifically labels neuronal α7-nAChRs.
[Show abstract][Hide abstract] ABSTRACT: There are only 2 currently available radioligands, 2-(18)F-FA and 6-(18)F-FA, for quantitative PET of the main cerebral subtype of nicotinic acetylcholine receptors (α4β2-nAChRs) in humans. Both exhibit slow distribution kinetics in the brain and require several hours for PET imaging. This makes PET of nAChRs with these radioligands logistically difficult and a serious burden for human subjects. The main purpose of this study was to preclinically evaluate (-)-2-(6-(18)F-fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-azabicyclo[2.2.1]heptane ((18)F-AZAN), our new radiolabeled antagonist of α4β2-nAChRs, that has high binding potential and rapid brain kinetics in baboons.
(18)F-AZAN was synthesized using a modified (18)F-FDG synthesis module. The regional distribution of (18)F-AZAN in the brain was evaluated in baseline and cytisine-blocking studies of 4 male Papio anubis baboons. PET modeling procedures were used for calculation of regional distribution volume (V(T)), nondisplaceable binding potential (BP(ND)), and receptor occupancy.
(18)F-AZAN rapidly entered the baboon brain, reached a steady state within 90 min after injection, and specifically labeled cerebral nAChRs. The peak radioactivity in the thalamus was 540 (percentage standardized uptake value) at 18 ± 7 min (n = 4) after bolus injection. Mathematical data analysis demonstrated that scanning for only 90 min is sufficient for determination of PET outcome variables (BP(ND), 3.2 [unitless] and V(T), 32-35 mL/mL in thalamus). The dose-dependent blocking experiments with cytisine demonstrated that (18)F-AZAN binds specifically with β2-containing (predominantly α4β2) nAChRs.
(18)F-AZAN specifically labels nAChRs in baboon brains with a high value of BP(ND) and it requires only 90 min of PET scanning to produce estimates of V(T) and BP(ND) in the various brain regions. The blocking of nAChRs with cytisine is dose-dependent and it showed that (18)F-AZAN is suitable for application in nicotinic drug evaluation. In summary, (18)F-AZAN is superior to 2-(18)F-FA and 6-(18)F-FA for imaging cerebral β2-containing nAChRs in baboons. Further evaluations of (18)F-AZAN in the human brain are under way.
Journal of Nuclear Medicine 12/2011; 53(1):121-9. DOI:10.2967/jnumed.111.092338 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: (18)F-fluorobenzyl triphenyl phosphonium (FBnTP) has recently been introduced as a myocardial perfusion PET agent. We used a rat model of transient coronary occlusion to determine the stability of the perfusion defect size over time and the magnitude of redistribution.
Wistar rats (n = 15) underwent thoracotomy and 2-min occlusion of the left coronary artery (LCA), followed by reperfusion. During occlusion, (18)F-FBnTP (92.5 MBq) and (201)Tl-thallium chloride (0.74 MBq) were injected intravenously. One minute before the animals were sacrificed at 5, 45, and 120 min after reperfusion, the LCA was occluded again and 2% Evans blue was injected intravenously to determine the ischemic territory. The hearts were excised, frozen, and sliced for serial dual-tracer autoradiography and histology. Dynamic in vivo (18)F-FBnTP PET was performed on a subgroup of animals (n = 4).
(18)F-FBnTP showed stable ischemic defects at all time points after tracer injection and reperfusion. The defects matched the blue dye defect (y = 0.97x+1.5, R(2) = 0.94, y = blue-dye defect, x = (18)F-FBnTP defect). Count density analysis showed no defect fill-in at 45 min but slightly increased activity at 120 min (LCA/remote uptake ratio = 0.19 ± 0.02, 0.19 ± 0.05, and 0.34 ± 0.06 at 5, 45, and 120 min, respectively, P < 0.05). For comparison, (201)Tl showed complete redistribution at 120 min (LCA/remote = 0.42 ± 0.04, 0.72 ± 0.03, and 0.97 ± 0.05 at 5, 45, and 120 min, respectively, P < 0.001). Persistence of the (18)F-FBnTP defect over time was confirmed by in vivo dynamic small-animal PET.
In a transient coronary occlusion model, perfusion defect size using the new PET agent (18)F-FBnTP remained stable for at least 45 min and matched the histologically defined ischemic area. This lack of significant redistribution suggests a sufficient time window for future clinical protocols with tracer injection remote from the scanner, such as in a stress testing laboratory or chest pain unit.
Journal of Nuclear Medicine 06/2011; 52(6):965-9. DOI:10.2967/jnumed.110.085993 · 6.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prior studies, all using SPECT techniques, failed to find any differences for dopamine transporter (DAT) in restless legs syndrome (RLS) subjects. The distinct pharmacokinetic properties associated with SPECT-determined DAT along with rapid biodynamic changes in DAT may, however, have missed membrane-bound DAT differences. The current studies assessed real-time DAT binding potentials (BP) in striatum of RLS patients using (11)C-methylphenidate and PET techniques.
RLS medications were stopped at least 11 days prior to the PET study. Clinical severity of RLS was also assessed. PET scans were performed at 2 different times of day (starting at 08:30 and 19:30) in separate groups of subjects. The primary outcome measure was total striatal DAT BP.
Thirty-six patients with primary RLS and 34 age- and gender-matched controls.
RLS subjects had significantly lower DAT binding in the striatum compared to controls on both the Day and the Night scans. DAT was decreased in putamen and caudate but not the ventral striatum of RLS subjects. There were no diurnal differences in DAT for the total group or for control and RLS separately. DAT BP did not correlate with any clinical measures of RLS.
The current study found a significant decrease in DAT BP in two independent studies. These results when viewed along with prior RLS SPECT and autopsy studies of DAT, and cell culture studies with iron deficiency and DAT, suggest that membrane-bound striatal DAT, but not total cellular DAT, may be decreased in RLS.
[Show abstract][Hide abstract] ABSTRACT: The peptide hormone ghrelin mediates through action on its receptor, the growth hormone secretagogue receptor (GHSR), and is known to play an important role in a variety of metabolic functions including appetite stimulation, weight gain, and suppression of insulin secretion. In light of the fact that obesity is one of the major health problems plaguing the modern society, the ghrelin signaling system continues to remain an important and attractive pharmacological target for the treatment of obesity. In vivo imaging of the GHSR could shed light on the mechanism by which ghrelin affects feeding behavior and thus offers a new therapeutic perspective for the development of effective treatments. Recently, a series of piperidine-substituted quinazolinone derivatives was reported to be selective and potent GHSR antagonists with high binding affinities. Described herein is the synthesis, in vitro, and in vivo evaluation of (S)-6-(4-fluorophenoxy)-3-((1-[(11)C]methylpiperidin-3-yl)methyl)-2-o-tolylquinazolin-4(3H)-one ([(11)C]1), a potential PET radioligand for imaging GHSR.
[Show abstract][Hide abstract] 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, [(11)C]OMAR (JHU75528), 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 [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) 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 [(11)C]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 V(T) 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 (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.
[Show abstract][Hide abstract] ABSTRACT: Recently, A-836339 [2,2,3,3-tetramethylcyclopropanecarboxylic acid [3-(2-methoxyethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]amide] (1) was reported to be a selective CB2 agonist with high binding affinity. Here we describe the radiosynthesis of [11C]A-836339 ([11C]1) via its desmethyl precursor as a candidate radioligand for imaging CB2 receptors with positron-emission tomography (PET). Whole body and the regional brain distribution of [11C]1 in control CD1 mice demonstrated that this radioligand exhibits specific uptake in the CB2-rich spleen and little specific in vivo binding in the control mouse brain. However, [11C]1 shows specific cerebral uptake in the lipopolysaccharide (LPS)-induced mouse model of neuroinflammation and in the brain areas with Abeta amyloid plaque deposition in a mouse model of Alzheimer's disease (APPswe/PS1dE9 mice). These data establish a proof of principle that CB2 receptors binding in the neuroinflammation and related disorders can be measured in vivo.