Publications by authors named "Joji Yui"

74 Publications

Radiosynthesis of [thiocarbonyl-C]disulfiram and its first PET study in mice.

Bioorg Med Chem Lett 2020 03 28;30(6):126998. Epub 2020 Jan 28.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

[Thiocarbonyl-C]disulfiram ([C]DSF) was synthesized via iodine oxidation of [C]diethylcarbamodithioic acid ([C]DETC), which was prepared from [C]carbon disulfide and diethylamine. The decay-corrected isolated radiochemical yield (RCY) of [C]DSF was greatly affected by the addition of unlabeled carbon disulfide. In the presence of carbon disulfide, the RCY was increased up to 22% with low molar activity (A, 0.27 GBq/μmol). On the other hand, [C]DSF was obtained in 0.4% RCY with a high A value (95 GBq/μmol) in the absence of carbon disulfide. The radiochemical purity of [C]DSF was always >98%. The first PET study on [C]DSF was performed in mice. A high uptake of radioactivity was observed in the liver, kidneys, and gallbladder. The uptake level and distribution pattern in mice were not significantly affected by the A value of the [C]DSF sample used. In vivo metabolite analysis showed the rapid decomposition of [C]DSF in mouse plasma.
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http://dx.doi.org/10.1016/j.bmcl.2020.126998DOI Listing
March 2020

[C]BCTC: Radiosynthesis and in vivo binding to transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor in the mouse trigeminal nerve.

Bioorg Med Chem Lett 2017 10 1;27(19):4521-4524. Epub 2017 Sep 1.

Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address:

The purpose of this study was to synthesize a new positron emission tomography radiotracer, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-[C]carboxamide ([C]BCTC, [C]1), and assess its in vivo binding to the transient receptor potential vanilloid subfamily member 1 (TRPV1) receptor in mice. [C]BCTC was synthesized by reacting the hydrochloride of 4-tertiarybutylaniline (2·HCl) with [C]phosgene ([C]COCl) to give isocyanate [C]4, followed by reaction with 4-(3-chloropyridin-2-yl)tetrahydropyrazine (3). [C]BCTC was obtained at a 16-20% radiochemical yield, based on the cyclotron-produced [C]CO (decay-corrected to the end of bombardment), with >98% radiochemical purity and 65-110GBq/μmol specific activity at the end of synthesis. An ex vivo biodistribution study in mice confirmed the specific binding of [C]BCTC to TRPV1 in the trigeminal nerve, which is a tissue with high TRPV1 expression.
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http://dx.doi.org/10.1016/j.bmcl.2017.08.061DOI Listing
October 2017

Synthesis and evaluation of 1-(cyclopropylmethyl)-4-(4-[C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([C]CMDC) for PET imaging of metabotropic glutamate receptor 2 in the rat brain.

Bioorg Med Chem 2017 02 23;25(3):1014-1021. Epub 2016 Dec 23.

Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address:

Brain metabotropic glutamate receptor 2 (mGluR2) has been proposed as a therapeutic target for the treatment of schizophrenia-like symptoms arising from increased glutamate transmission in the forebrain. However, there does not exist a reliable tool for the study of mGluR2 in human neuroimaging. The purpose of this study was to radiosynthesize 1-(cyclopropylmethyl)-4-(4-[C]methoxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([C]CMDC) and evaluate its potential as a positron emission tomography (PET) radiotracer for imaging mGluR2 in the rat brain. CMDC, a positive allosteric modulator of mGluR2, showed potent functional activity (EC: 98nM) for human mGluR2 in vitro. [C]CMDC was synthesized by O-[C]methylation of 1-(cyclopropylmethyl)-4-(4-hydroxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) with [C]methyl iodide. [C]CMDC (2.2±0.9GBq; n=20) was obtained from [C]CO of 14.0-17.8GBq with >98% radiochemical purity and 86-150GBq/μmol specific activity at the end of synthesis. In vitro autoradiography indicated that [C]CMDC binding was expressed (>50% of total binding) in mGluR2-rich brain regions including the cerebral cortex, striatum and hippocampus. However, small-animal PET showed low in vivo specific binding of [C]CMDC in the rat brain. While [C]CMDC has limited potential as a PET tracer for brain mGluR2, it can be used to develop new radiotracers with improved behaviors.
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http://dx.doi.org/10.1016/j.bmc.2016.12.011DOI Listing
February 2017

A useful PET probe [C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I-imidazoline receptors in the hypothalamus.

Nucl Med Biol 2017 02 26;45:1-7. Epub 2016 Oct 26.

Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

Introduction: A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [C]BU99008, a more potent PET probe for I-imidazoline receptors (IRs) imaging, with a conventional SA (mean 76GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for IRs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of IRs.

Methods: [C]BU99008 was prepared by [C]methylation of N-desmethyl precursor with [C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats.

Results: [C]BU99008 with ultra-high SA in the range of 5400-16,600GBq/μmol were successfully synthesized (n=7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [C]BU99008 at 30min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC) in the hypothalamus of rats injected with [C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [C]BU99008 with ultra-high SA (86% of total binding) for IR was higher than that of conventional SA (76% of total binding).

Conclusion: A PET study using [C]BU99008 with ultra-high SA would thus contribute to the detection of small changes in or small regions with IR expression and hence may be useful in elucidating new functions of IR.
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http://dx.doi.org/10.1016/j.nucmedbio.2016.10.005DOI Listing
February 2017

Synthesis and Preclinical Evaluation of Sulfonamido-based [(11)C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipase.

Theranostics 2016 21;6(8):1145-59. Epub 2016 May 21.

1. Gordon Center of Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA, 02114, USA.

Monoacylglycerol lipase (MAGL) is a 33 kDa member of the serine hydrolase superfamily that preferentially degrades 2-arachidonoylglycerol (2-AG) to arachidonic acid in the endocannabinoid system. Inhibition of MAGL is not only of interest for probing the cannabinoid pathway but also as a therapeutic and diagnostic target for neuroinflammation. Limited attempts have been made to image MAGL in vivo and a suitable PET ligand for this target has yet to be identified and is urgently sought to guide small molecule drug development in this pathway. Herein we synthesized and evaluated the physiochemical properties of an array of eleven sulfonamido-based carbamates and ureas with a series of terminal aryl moieties, linkers and leaving groups. The most potent compounds were a novel MAGL inhibitor, N-((1-(1H-1,2,4-triazole-1-carbonyl)piperidin-4-yl) methyl)-4-chlorobenzenesulfonamide (TZPU; IC50 = 35.9 nM), and the known inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(((4-chlorophenyl)sulfonamido) methyl)piperidine-1-carboxylate (SAR127303; IC50 = 39.3 nM), which were also shown to be selective for MAGL over fatty acid amide hydrolase (FAAH), and cannabinoid receptors (CB1 & CB2). Both of these compounds were radiolabeled with carbon-11 via [(11)C]COCl2, followed by comprehensive ex vivo biodistribution and in vivo PET imaging studies in normal rats to determine their brain permeability, specificity, clearance and metabolism. Whereas TZPU did not show adequate specificity to warrant further evaluation, [(11)C]SAR127303 was advanced for preliminary PET neuroimaging studies in nonhuman primate. The tracer showed good brain permeability (ca. 1 SUV) and heterogeneous regional brain distribution which is consistent with the distribution of MAGL.
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http://dx.doi.org/10.7150/thno.15257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893642PMC
October 2017

Benzyl [(11)C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice.

J Med Chem 2016 06 6;59(12):5847-56. Epub 2016 Jun 6.

Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues. Among the compounds screened, benzyl [(11)C]hippurate showed favorable hydrolysis rates and uptake properties in the target tissues of mice. Subsequent evaluation using transporter knockout mice revealed that radioactivity was retained in the brain and heart of Oat3(-/-) and Mrp4(-/-) mice, respectively, compared with that of control mice after the intravenous administration of benzyl [(11)C]hippurate. Benzyl [(11)C]hippurate could therefore be used as a probe for estimating the activities of OAT3 and MRP4 in mouse brain and heart, respectively.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00454DOI Listing
June 2016

Efficient radiosynthesis and non-clinical safety tests of the TSPO radioprobe [(18)F]FEDAC: Prerequisites for clinical application.

Nucl Med Biol 2016 07 26;43(7):445-53. Epub 2016 Apr 26.

Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.

Introduction: [(18)F]FEDAC ([(18)F]1) has potent binding affinity and selectivity for translocator protein (18kDa, TSPO), and has been used to noninvasively visualize neuroinflammation, lung inflammation, acute liver damage, nonalcoholic fatty liver disease, and liver fibrosis. We had previously synthesized [(18)F]1 in two steps: (i) preparation of [(18)F]fluoroethyl bromide and (ii) coupling of [(18)F]fluoroethyl bromide with the appropriate precursor (2) for labeling. In this study, to clinically utilize [(18)F]1 as a PET radiopharmaceutical and to transfer the production technique of [(18)F]1 to other PET centers, we simplified its preparation by using a direct, one-step, tosyloxy-for-fluorine substitution. We also performed an acute toxicity study as a major non-clinical safety test, and determined radiometabolites using human liver microsomes.

Methods: [(18)F]1 was prepared via direct (18)F-fluorination by heating the corresponding tosylated derivative (3) with [(18)F]fluoride as its Kryptofix 222 complex in dimethyl sulfoxide at 110°C for 15min, following by HPLC purification. Non-clinical safety tests were performed for the extended single-dose toxicity study in rats, and for the in vitro metabolite analysis with human liver microsomal incubation.

Results: High quality batches of [(18)F]1, compatible with clinical applications, were obtained. At the end of irradiation, the decay-corrected radiochemical yield of [(18)F]1 using 1 and 5mg of precursor based on [(18)F]fluoride was 18.5±7.9% (n=10) and 52.0±5.8% (n=3), respectively. A single-dose of [(18)F]1 did not show toxicological effects for 14 days after the injection in male and female rats. In human liver microsomal incubations, [(18)F]1 was easily metabolized to [(18)F]desbenzyl-FEDAC ([(18)F]10) by CYPs (4.2% of parent compound left 60min after incubation).

Conclusion: We successfully synthesized clinical grade batches of [(18)F]1 and verified the absence of innocuity of this radiotracer. [(18)F]1 will be used to first-in-human studies in our facility.
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http://dx.doi.org/10.1016/j.nucmedbio.2016.04.004DOI Listing
July 2016

Synthesis and Evaluation of Novel Radioligands Based on 3-[5-(Pyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor Subtype 5.

J Med Chem 2016 04 13;59(8):3980-90. Epub 2016 Apr 13.

Department of Radiopharmaceuticals Development, Radiological Science Research and Development Directorate, National Institutes for Quantum and Radiological Science and Technology , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

We found out 3-[5-(pyridin-2-yl)-2H-tetrazol-2-yl]benzonitrile analogues as the candidate for positron emission tomography (PET) imaging agents of metabotropic glutamate receptor subtype 5 (mGluR5). Among these compounds, 3-methyl-5-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile (10) exhibited high binding affinity (Ki = 9.4 nM) and moderate lipophilicity (cLogD, 2.4). Subsequently, [(11)C]10 was radiosynthesized at 25 ± 14% radiochemical yield (n = 11) via C-[(11)C]methylation of the arylstannyl precursor 15 with [(11)C]methyl iodide. In vitro autoradiography and PET assessments using [(11)C]10 showed high specific binding in the striatum and hippocampus, two brain regions enriched with mGluR5. Moreover, test-retest PET studies with [(11)C]10 indicated high reliability to quantify mGluR5 density, such as the intraclass correlation coefficient (0.90) and Pearson r (0.91) in the striatum of rat brain. We demonstrated that [(11)C]10 is a useful PET ligand for imaging and quantitative analysis of mGluR5. Furthermore, [(11)C]10 might be modified using its skeleton as a lead compound.
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http://dx.doi.org/10.1021/acs.jmedchem.6b00209DOI Listing
April 2016

Dynamic Changes in Striatal mGluR1 But Not mGluR5 during Pathological Progression of Parkinson's Disease in Human Alpha-Synuclein A53T Transgenic Rats: A Multi-PET Imaging Study.

J Neurosci 2016 Jan;36(2):375-84

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.

Unlabelled: Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by resting tremor and movement deficits. Group I metabotropic glutamate receptor subtypes 1 and 5 (mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated the in vivo roles of mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging in A53T transgenic (A53T-Tg) rats expressing an abnormal human α-synuclein (ASN) gene. A53T-Tg rats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [(11)C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]methylbenzamide), a selective PET ligand for mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPND values for (E)-[(11)C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[(11)C]methyloxime], a specific PET ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal mGluR1 BPND values also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in mGluR1 BPND values were correlated with decreases in BPND values for [(18)F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2β-carbo-[(18)F]fluoroethoxy-3β-(4-methylphenyl) nortropane], a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model.

Significance Statement: Synaptic signaling by glutamate, the principal excitatory neurotransmitter in the brain, is modulated by group I metabotropic glutamate receptors, including the mGluR1 and mGluR5 subtypes. In the brain, mGluR1 and mGluR5 have distinct functional roles and regional distributions. Their roles in brain pathology, however, are not well characterized. Using longitudinal PET imaging in a chronic rat model of PD, we demonstrated that expression of mGluR1, but not mGluR5, dynamically changed in the striatum accompanying pathological PD progression. These findings imply that monitoring mGluR1 in vivo may provide beneficial information to further understand central nervous system disorders.
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http://dx.doi.org/10.1523/JNEUROSCI.2289-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602033PMC
January 2016

N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide: A promising positron emission tomography ligand for fatty acid amide hydrolase.

Bioorg Med Chem 2016 Feb 15;24(4):627-34. Epub 2015 Dec 15.

Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

To visualize fatty acid amide hydrolase (FAAH) in brain in vivo, we developed a novel positron emission tomography (PET) ligand N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[(11)C]methylphenyl)thiazol-2-yl]-1-carboxamide ([(11)C]DFMC, [(11)C]1). DFMC (1) was shown to have high binding affinity (IC50: 6.1nM) for FAAH. [(11)C]1 was synthesized by C-(11)C coupling reaction of arylboronic ester 2 with [(11)C]methyl iodide in the presence of Pd catalyst. At the end of synthesis, [(11)C]1 was obtained with a radiochemical yield of 20±10% (based on [(11)C]CO2, decay-corrected, n=5) and specific activity of 48-166GBq/μmol. After the injection of [(11)C]1 in mice, high uptake of radioactivity (>2% ID/g) was distributed in the lung, liver, kidney, and brain, organs with high FAAH expression. PET images of rat brains for [(11)C]1 revealed high uptakes in the cerebellar nucleus (SUV=2.4) and frontal cortex (SUV=2.0), two known brain regions with high FAAH expression. Pretreatment with the FAAH-selective inhibitor URB597 reduced the brain uptake. Higher than 90% of the total radioactivity in the rat brain was irreversible at 30min after the radioligand injection. The present results indicate that [(11)C]1 is a promising PET ligand for imaging of FAAH in living brain.
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http://dx.doi.org/10.1016/j.bmc.2015.12.026DOI Listing
February 2016

Radiosynthesis and evaluation of 5-methyl-N-(4-[(11)C]methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine ([(11)C]ADX88178) as a novel radioligand for imaging of metabotropic glutamate receptor subtype 4 (mGluR4).

Bioorg Med Chem Lett 2016 Jan 7;26(2):370-374. Epub 2015 Dec 7.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

ADX88178 (1) has been recently developed as a potent positive allosteric modulator for metabotropic glutamate receptor 4 (mGluR4). The aim of this study was to develop [(11)C]1 as a novel positron emission tomography ligand and to evaluate its binding ability for mGluR4. Using stannyl precursor 3, [(11)C]1 was efficiently synthesized by introducing an [(11)C]methyl group into a pyrimidine ring via C-(11)C coupling and deprotection reactions, in 16±6% radiochemical yield (n=10). At the end of synthesis, 0.54-1.10GBq of [(11)C]1 was acquired with >98% radiochemical purity and 90-120GBq/μmol of specific activity. In vitro autoradiography and ex vivo biodistribution study in rat brains showed specific binding of [(11)C]1 in the cerebellum, striatum, thalamus, cerebral cortex, and medulla oblongata, which showed dose-dependent decreases by administration with multi-dose of unlabeled 1.
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http://dx.doi.org/10.1016/j.bmcl.2015.12.008DOI Listing
January 2016

Utility of Translocator Protein (18 kDa) as a Molecular Imaging Biomarker to Monitor the Progression of Liver Fibrosis.

Sci Rep 2015 Nov 27;5:17327. Epub 2015 Nov 27.

Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Hepatic fibrosis is the wound healing response to chronic hepatic injury caused by various factors. In this study, we aimed to evaluate the utility of translocator protein (18 kDa) (TSPO) as a molecular imaging biomarker for monitoring the progression of hepatic fibrosis to cirrhosis. Model rats were induced by carbon tetrachloride (CCl4), and liver fibrosis was assessed. Positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]-acetamide ([(18)F]FEDAC), a radioprobe specific for TSPO, was used for noninvasive visualisation in vivo. PET scanning, immunohistochemical staining, ex vivo autoradiography, and quantitative reverse-transcription polymerase chain reaction were performed to elucidate the relationships among radioactivity uptake, TSPO levels, and cellular sources enriching TSPO expression in damaged livers. PET showed that uptake of radioactivity in livers increased significantly after 2, 4, 6, and 8 weeks of CCl4 treatment. Immunohistochemistry demonstrated that TSPO was mainly expressed in macrophages and hepatic stellate cells (HSCs). TSPO-expressing macrophages and HSCs increased with the progression of liver fibrosis. Interestingly, the distribution of radioactivity from [(18)F]FEDAC was well correlated with TSPO expression, and TSPO mRNA levels increased with the severity of liver damage. TSPO was a useful molecular imaging biomarker and could be used to track the progression of hepatic fibrosis to cirrhosis with PET.
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http://dx.doi.org/10.1038/srep17327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661446PMC
November 2015

Development of 1-N-(11)C-Methyl-L- and -D-Tryptophan for pharmacokinetic imaging of the immune checkpoint inhibitor 1-Methyl-Tryptophan.

Sci Rep 2015 Nov 10;5:16417. Epub 2015 Nov 10.

Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

1-Methyl-tryptophan (1MTrp) is known as a specific inhibitor targeting the immune-checkpoint protein indoleamine-2,3-dioxygenase, in two stereoisomers of levorotary (L) and dextrorotary (D). A long-standing debate exists in immunology and oncology: which stereoisomer has the potential of antitumor immunotherapy. Herein, we developed two novel radioprobes, 1-N-(11)C-methyl-L- and -D-tryptophan ((11)C-L-1MTrp and (11)C-D-1MTrp), without modifying the chemical structures of the two isomers, and investigated their utility for pharmacokinetic imaging of the whole body. (11)C-L-1MTrp and (11)C-D-1MTrp were synthesized rapidly with radiochemical yields of 47 ± 6.3% (decay-corrected, based on (11)C-CO2), a radiochemical purity of >98%, specific activity of 47-130 GBq/μmol, and high enantiomeric purity. PET/CT imaging in rats revealed that for (11)C-L-1MTrp, the highest distribution of radioactivity was observed in the pancreas, while for (11)C-D-1MTrp, it was observed in the kidney. Ex vivo biodistribution confirmed the PET/CT results, indicating the differences in pharmacokinetics between the two isomers. Both (11)C-L-1MTrp and (11)C-D-1MTrp are therefore useful PET probes for delineating the distribution and action of the checkpoint inhibitor 1MTrp in vivo. This study represents the first step toward using whole-body and real-time insight to disentangle the antitumor potential of the two stereoisomers of 1MTrp, and it can facilitate the development of 1MTrp immunotherapy.
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http://dx.doi.org/10.1038/srep16417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639751PMC
November 2015

Synthesis and Preliminary PET Imaging Studies of a FAAH Radiotracer ([¹¹C]MPPO) Based on α-Ketoheterocyclic Scaffold.

ACS Chem Neurosci 2016 Jan 17;7(1):109-18. Epub 2015 Nov 17.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.

Fatty acid amide hydrolase (FAAH) is one of the principle enzymes for metabolizing endogenous cannabinoid neurotransmitters such as anandamide, and thus regulates endocannabinoid (eCB) signaling. Selective pharmacological blockade of FAAH has emerged as a potential therapy to discern the endogenous functions of anandamide-mediated eCB pathways in anxiety, pain, and addiction. Quantification of FAAH in the living brain by positron emission tomography (PET) would help our understanding of the endocannabinoid system in these conditions. While most FAAH radiotracers operate by an irreversible ("suicide") binding mechanism, a FAAH tracer with reversibility would facilitate quantitative analysis. We have identified and radiolabeled a reversible FAAH inhibitor, 7-(2-[(11)C]methoxyphenyl)-1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one ([(11)C]MPPO) in 13% radiochemical yield (nondecay corrected) with >99% radiochemical purity and 2 Ci/μmol (74 GBq/μmol) specific activity. The tracer showed moderate brain uptake (0.8 SUV) with heterogeneous brain distribution. However, blocking studies with a potent FAAH inhibitor URB597 demonstrated a low to modest specificity to the target. Measurement of lipophilicity, metabolite, and efflux pathway analysis were also performed to study the pharmacokinetic profile of [(11)C]MPPO. In all, we reported an efficient radiolabeling and preliminary evaluation of the first-in-class FAAH inhibitor [(11)C]MPPO with α-ketoheterocyclic scaffold.
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http://dx.doi.org/10.1021/acschemneuro.5b00248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876717PMC
January 2016

Identification of a major radiometabolite of [11C]PBB3.

Nucl Med Biol 2015 Dec 2;42(12):905-10. Epub 2015 Sep 2.

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

Introduction: [(11)C]PBB3 is a clinically used positron emission tomography (PET) probe for in vivo imaging of tau pathology in the brain. Our previous study showed that [(11)C]PBB3 was rapidly decomposed to a polar radiometabolite in the plasma of mice. For the pharmacokinetic evaluation of [(11)C]PBB3 it is important to elucidate the characteristics of radiometabolites. In this study, we identified the chemical structure of a major radiometabolite of [(11)C]PBB3 and proposed the metabolic pathway of [(11)C]PBB3.

Methods: Carrier-added [(11)C]PBB3 was injected into a mouse for in vivo metabolite analysis. The chemical structure of a major radiometabolite was identified using LC-MS. Mouse and human liver microsomes and liver S9 samples were incubated with [(11)C]PBB3 in vitro. In silico prediction software was used to assist in the determination of the metabolite and metabolic pathway of [(11)C]PBB3.

Results: In vivo analysis showed that the molecular weight of a major radiometabolite of [(11)C]PBB3, which was called as [(11)C]M2, was m/z 390 [M+H(+)]. In vitro analysis assisted by in silico prediction showed that [(11)C]M2, which was not generated by cytochrome P450 enzymes (CYPs), was generated by sulfated conjugation mediated by a sulfotransferase.

Conclusion: The major radiometabolite, [(11)C]M2, was identified as a sulfated conjugate of [(11)C]PBB3. [(11)C]PBB3 was metabolized mainly by a sulfotransferase and subsidiarily by CYPs.
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http://dx.doi.org/10.1016/j.nucmedbio.2015.08.006DOI Listing
December 2015

Development of the Fibronectin-Mimetic Peptide KSSPHSRN(SG)5RGDSP as a Novel Radioprobe for Molecular Imaging of the Cancer Biomarker α5β1 Integrin.

Biol Pharm Bull 2015 15;38(11):1722-31. Epub 2015 Aug 15.

Molecular Imaging Center, National Institute of Radiological Sciences.

α5β1 Integrin, a fibronectin receptor, is becoming a pertinent therapeutic target and a promising prognostic biomarker for cancer patients. The aim of this study was to functionalize an α5β1-specific fibronectin-mimetic peptide sequence KSSPHSRN(SG)5RGDSP (called PR_b) as a positron emission tomography (PET) probe. PR_b was modified by addition of a β-alanine residue, conjugated with 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and radiolabeled with (18)F based on the chelation of (18)F-aluminum fluoride. A control probe was produced by glycine to alanine substitution in the RGD motif of PR_b. Cell binding and blocking assays, autoradiographic evaluation of tissue binding and blocking, dynamic PET scans, and a biodistribution study were conducted using cell lines and murine tumor models with determined expression levels of α5β1 and other related integrins. (18)F-PR_b was produced with a labeling yield of 22.3±1.9% based on (18)F-F(-), a radiochemical purity of >99%, and a specific activity of 30-70 GBq/µmol; it exhibited α5β1-binding activity and specificity in vitro, ex vivo, and in vivo, and had a rapid blood clearance and a predominant renal excretion pathway. In vivo α5β1-positive tumors could be clearly visualized by (18)F-PR_b PET imaging. Both imaging and biodistribution studies suggested higher uptake of (18)F-PR_b in α5β1-positive tumors than in α5β1-negative tumors and higher α5β1-positive tumor uptake of (18)F-PR_b than the control probe. In contrast, there was no significant difference seen in the contralateral muscle uptake. A PET radioprobe, (18)F-PR_b, was developed de novo and potentially can be used for noninvasive detection of α5β1 expression in tumors.
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http://dx.doi.org/10.1248/bpb.b15-00344DOI Listing
August 2016

[18F]FEBMP: Positron Emission Tomography Imaging of TSPO in a Model of Neuroinflammation in Rats, and in vitro Autoradiograms of the Human Brain.

Theranostics 2015 26;5(9):961-9. Epub 2015 May 26.

1. Molecular Imaging Centre, National Institute of Radiological Sciences, Chiba, Japan.

We evaluated the efficacy of 2-[5-(4-[(18)F]fluoroethoxy-2-oxo-1,3-benzoxazol-3(2H)-yl)-N-methyl-N-phenylacetamide] ([(18)F]FEBMP) for positron emission tomography (PET) imaging of translocator protein (18 kDa, TSPO). Dissection was used to determine the distribution of [(18)F]FEBMP in mice, while small-animal PET and metabolite analysis were used for a rat model of focal cerebral ischemia. [(18)F]FEBMP showed high radioactivity uptake in mouse peripheral organs enriched with TSPO, and relatively high initial brain uptake (2.67 ± 0.12% ID/g). PET imaging revealed an increased accumulation of radioactivity in the infarcted striatum, with a maximum ratio of 3.20 ± 0.12, compared to non-injured striatum. Displacement with specific TSPO ligands lowered the accumulation levels in infarcts to those on the contralateral side. This suggests that the increased accumulation reflected TPSO-specific binding of [(18)F]FEBMP in vivo. Using a simplified reference tissue model, the binding potential on the infarcted area was 2.72 ± 0.27. Metabolite analysis in brain tissues showed that 83.2 ± 7.4% and 76.4 ± 2.1% of radioactivity was from intact [(18)F]FEBMP at 30 and 60 min, respectively, and that this ratio was higher than in plasma (8.6 ± 1.9% and 3.9 ± 1.1%, respectively). In vitro autoradiography on postmortem human brains showed that TSPO rs6971 polymorphism did not affect binding sites for [(18)F]FEBMP. These findings suggest that [(18)F]FEBMP is a promising new tool for visualization of neuroinflammation.
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http://dx.doi.org/10.7150/thno.12027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493534PMC
March 2016

Improved Visualization and Specific Binding for Metabotropic Glutamate Receptor Subtype 1 (mGluR1) Using [11C]ITMM with Ultra-High Specific Activity in Small-Animal PET.

PLoS One 2015 15;10(6):e0130006. Epub 2015 Jun 15.

Molucular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

Metabotropic glutamate receptor subtype 1 (mGluR1) is a crucial target in the development of new medications to treat central nervous system (CNS) disorders. Recently, we developed N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[11C]methoxy-N-methyl-benzamide ([11C]ITMM) as a useful positron emission tomography (PET) probe for mGluR1 in clinical studies. Here, we aimed to improve visualization and threshold of specific binding for mGluR1 using [11C]ITMM with ultra-high specific activity (SA) of > 3,500 GBq/μmol in rat brains. A two-tissue compartment model indicated large differences between the two SAs in the constants k3 and k4, representing binding ability for mGluR1, while constants K1 and k2 showed no differences. The total distribution volume (VT) values of conventional and ultra-high SA were 9.1 and 11.2 in the thalamus, 7.7 and 9.7 in the striatum, and 6.4 and 8.5 mL/cm3 in the substantia nigra, respectively. The specific binding of [11C]ITMM with ultra-high SA was significantly higher than the conventional SA, especially in the basal ganglia. Parametric PET images scaled with VT of the ultra-high SA clearly identified regional differences in the rat brain. In conclusion, PET studies using [11C]ITMM with ultra-high SA could sufficiently improve visualization and specific binding for mGluR1, which could help further understanding for mGluR1 functions in CNS disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130006PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468202PMC
April 2016

Radiosynthesis and preliminary PET evaluation of glycogen synthase kinase 3β (GSK-3β) inhibitors containing [(11)C]methylsulfanyl, [(11)C]methylsulfinyl or [(11)C]methylsulfonyl groups.

Bioorg Med Chem Lett 2015 Aug 3;25(16):3230-3. Epub 2015 Jun 3.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

Three compounds 1-3 containing methyl-sufanyl, sufinyl, or sulfonyl groups are strong inhibitors of glycogen synthase kinase 3β (GSK-3β), an enzyme associated with Alzheimer's disease. We labeled 1-3 with (11)C for a positron emission tomography (PET) brain imaging study. A novel thiophenol precursor 4 for radiosynthesis was prepared by reacting sulfoxide 2 with trifluoroacetic anhydride. [(11)C]1 was synthesized by reacting 4 with [(11)C]methyl iodide in 52 ± 5% radiochemical yield (n = 5, based on [(11)C]CO2, corrected for decay). Oxidation of [(11)C]1 with Oxone® produced [(11)C]2 and [(11)C]3, respectively. PET with [(11)C]1 and [(11)C]3 showed 2 fold higher brain uptake of radioactivity in a mouse model of cold water stress in which GSK-3β expression was increased, than in the controls.
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http://dx.doi.org/10.1016/j.bmcl.2015.05.085DOI Listing
August 2015

Synthesis and evaluation of 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-[11C]methylbenzamide for imaging of metabotropic glutamate 1 receptor in melanoma.

J Med Chem 2015 Feb 30;58(3):1513-23. Epub 2015 Jan 30.

Molecular Imaging Center, National Institute of Radiological Sciences , 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.

Metabotropic glutamate 1 (mGlu1) receptor is found not only in the brain but also in melanomas and breast cancers. mGlu1 is a promising target for molecular imaging-based diagnosis and treatment of melanoma because its overexpression induces melanocyte carcinogenesis. Here we developed three PET tracers: 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol- 2-yl]-N-[(11)C]methylbenzamide ([(11)C]4-6), which exhibited high uptake in target tumor and decreased uptake in nontarget brain tissues. In vitro binding assay indicated high to moderate binding affinities of 4-6 (Ki, 22-143 nM) for mGlu1 receptor. In vivo biodistribution studies in mice implanted with B16F10 melanoma cells confirmed high radioactive uptake in tumor and low uptake in blood, skin, and muscles. Inhibition of mGlu1 receptor using an mGlu1-selective ligand led to reduced radioactive uptake in the tumor. [(11)C]6 displayed the highest ratio of uptake between tumor and nontarget tissue and may prove useful as a PET tracer for mGlu1 imaging in melanoma.
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http://dx.doi.org/10.1021/jm501845nDOI Listing
February 2015

In vivo evaluation of a new ¹⁸F-labeled PET ligand, [¹⁸F]FEBU, for the imaging of I₂-imidazoline receptors.

Nucl Med Biol 2015 Apr 26;42(4):406-12. Epub 2014 Dec 26.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.

Introduction: The functions of I₂-imidazoline receptors (I₂Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I₂R ligands have been developed, of which [(11)C]FTIMD and [(11)C]BU99008 were evaluated as PET I₂R imaging ligands in monkeys, no human PET imaging study using an I₂R-selective PET ligand has been conducted yet. Thus, we synthesized an (18)F-labeled I₂R-selective ligand (BU99018 or FEBU, Ki for I₂Rs=2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I₂R PET imaging ligand.

Methods: [(18)F]FEBU was synthesized by the reaction of its precursor and [(18)F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively.

Results: [(18)F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation (n=10) based on (18)F(-)). The specific activity at end of synthesis (EOS) was 40-147 TBq/mmol (n=10). The radiochemical purity was >99% at EOS and remained >99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I₂R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I₂R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection.

Conclusion: [(18)F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I₂Rs in rats and mice.
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http://dx.doi.org/10.1016/j.nucmedbio.2014.12.014DOI Listing
April 2015

Development of [(11)C]MFTC for PET imaging of fatty acid amide hydrolase in rat and monkey brains.

ACS Chem Neurosci 2015 Feb 26;6(2):339-46. Epub 2014 Nov 26.

Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.

We developed 2-methylpyridin-3-yl-4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine-1-[(11)C]carboxylate ([(11)C]MFTC) as a promising PET tracer for in vivo imaging of fatty acid amide hydrolase (FAAH) in rat and monkey brains. [(11)C]MFTC was synthesized by reacting 3-hydroxy-2-methylpyridine (2) with [(11)C]phosgene ([(11)C]COCl2), followed by reacting with 4-(5-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)piperidine (3), with a 20 ± 4.6% radiochemical yield (decay-corrected, n = 30) based on [(11)C]CO2 and 40 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in FAAH-rich organs, including the lung, liver, and kidneys. Positron emission tomography (PET) summation images of rat brains showed high radioactivity in the frontal cortex, cerebellum, and hippocampus, which was consistent with the regional distribution pattern of FAAH in rodent brain. Pretreatment with MFTC or FAAH-selective URB597 significantly reduced the uptake in the brain. PET imaging of monkey brain showed relatively high uptake in the whole brain, particularly in the occipital cortex, which was also inhibited by treatment with MFTC or URB597. More than 96% of the total radioactivity was irreversible in the brain homogenate of rats 5 min after the radiotracer injection. The specific in vivo FAAH binding indicates that [(11)C]MFTC is a promising PET tracer for visualizing FAAH in the brain.
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http://dx.doi.org/10.1021/cn500269gDOI Listing
February 2015

Synthesis and evaluation of new (18)F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain.

Org Biomol Chem 2014 Dec 23;12(47):9621-30. Epub 2014 Oct 23.

Molecular Imaging Centre, National Institute of Radiological Sciences, Inage-ku, Chiba 263-8555, Japan.

The visualization of the activated microglia/TSPO is one of the main aspects of neuroimaging. Here we describe two new (18)F-labelled molecules, 2-[5-(4-[(18)F]fluoroethoxyphenyl)- ([(18)F]2) and 2-[5-(4-[(18)F]fluoropropyloxyphenyl)- ([(18)F]3) -2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide as novel PET ligands for imaging the translocator protein (18 kDa, TSPO) in the brain. The three-D pharmacophore evaluation and docking studies suggested their high affinity for the TSPO and in vitro binding assays of the TSPO showed binding affinities 6.6 ± 0.7 nM and 16.7 ± 2.5 nM for 2 and 3, respectively. The radiochemical yields for [(18)F]2 and [(18)F]3 were found to be 22 ± 4% (n = 8) and 5 ± 2% (n = 5), respectively at EOB. The radiochemical purity for both was found ≥98% and the specific activity was in the range of 98-364 GBq μmol(-1) at EOS. In vitro autoradiography with an ischemic rat brain showed significantly increased binding on the ipsilateral side compared to the contralateral side. The specificity of [(18)F]2 and [(18)F]3 for binding TSPO was confirmed using the TSPO ligands PK11195 and MBMP. The biodistribution patterns of both PET ligands were evaluated in normal mice by 1 h dynamic PET imaging. In the brain, regional radioactivity reached the maximum very rapidly within 0-4 min for both ligands, similar to (R)[(11)C]PK11195. The metabolite study of [(18)F]2 also favoured a more favourable profile for quantification in comparison to (R)[(11)C]PK11195. In summary, these data indicated that [(18)F]2 and [(18)F]3 have good potential to work as PET ligands, therefore there are merits to use these radioligands for the in vivo evaluation in animal models to see their efficacy in the living brain.
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http://dx.doi.org/10.1039/c4ob01933dDOI Listing
December 2014

Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology.

J Nucl Med 2014 Sep 24;55(9):1532-8. Epub 2014 Jun 24.

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan

Unlabelled: 2-((1E,3E)-4-(6-((11)C-methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ((11)C-PBB3) is a clinically useful PET probe that we developed for in vivo imaging of tau pathology in the human brain. To ensure the availability of this probe among multiple PET facilities, in the present study we established protocols for the radiosynthesis and quality control of (11)C-PBB3 and for the characterization of its photoisomerization, biodistribution, and metabolism.

Methods: (11)C-PBB3 was synthesized by reaction of the tert-butyldimethylsilyl desmethyl precursor ( 1: ) with (11)C-methyl iodide using potassium hydroxide as a base, followed by deprotection. Photoisomerization of (11)C-PBB3 under fluorescent light was determined. The biodistribution and metabolite analysis of (11)C-PBB3 was determined in mice using the dissection method.

Results: (11)C-PBB3 was synthesized with 15.4% ± 2.8% radiochemical yield (decay-corrected, n = 50) based on the cyclotron-produced (11)C-CO2 and showed an averaged synthesis time of 35 min from the end of bombardment. The radiochemical purity and specific activity of (11)C-PBB3 were 98.0% ± 2.3% and 180.2 ± 44.3 GBq/μmol, respectively, at the end of synthesis (n = 50). (11)C-PBB3 showed rapid photoisomerization, and its radiochemical purity decreased to approximately 50% at 10 min after exposure to fluorescent light. After the fluorescent light was switched off, (11)C-PBB3 retained more than 95% radiochemical purity over 60 min. A suitable brain uptake (1.92% injected dose/g tissue) of radioactivity was observed at 1 min after the probe injection, which was followed by rapid washout from the brain tissue. More than 70% of total radioactivity in the mouse brain homogenate at 5 min after injection represented the unchanged (11)C-PBB3, despite its rapid metabolism in the plasma.

Conclusion: (11)C-PBB3 was produced with sufficient radioactivity and high quality, demonstrating its clinical utility. The present results of radiosynthesis, photoisomerization, biodistribution, and metabolite analysis could be helpful for the reliable production and application of (11)C-PBB3 in diverse PET facilities.
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http://dx.doi.org/10.2967/jnumed.114.139550DOI Listing
September 2014

[(11)C-carbonyl]CEP-32496: radiosynthesis, biodistribution and PET study of brain uptake in P-gp/BCRP knockout mice.

Bioorg Med Chem Lett 2014 Aug 2;24(15):3574-7. Epub 2014 Jun 2.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan. Electronic address:

CEP-32496 is a novel, orally active serine/threonine-protein kinase B-raf (BRAF) (V600E) kinase inhibitor that is being investigated in clinical trials for the treatment of some cancers in patients. In this study, we developed [(11)C-carbonyl]CEP-32496 as a novel positron emission tomography (PET) probe to study its biodistribution in the whole bodies of mice. [(11)C]CEP-32496 was synthesized by the reaction of 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine hydrochloride (1·HCl) with [(11)C]phosgene, followed by treatment with 3-(6,7-dimethoxyquinozolin-4-yloxy)aniline (2). Small-animal PET studies with [(11)C]CEP-32496 indicated that radioactivity levels (AUC0-90 min, SUV×min) accumulated in the brains of P-gp/BCRP knockout mice at a 8-fold higher rate than in the brains of wild-type mice.
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http://dx.doi.org/10.1016/j.bmcl.2014.05.045DOI Listing
August 2014

PET brain kinetics studies of (11)C-ITMM and (11)C-ITDM,radioprobes for metabotropic glutamate receptor type 1, in a nonhuman primate.

Am J Nucl Med Mol Imaging 2014 25;4(3):260-9. Epub 2014 Apr 25.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences Inage-ku, Chiba, Japan.

The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm(-3) for (11)C-ITMM and 3.6 mL∙cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999406PMC
May 2014

Molecular imaging of ectopic metabotropic glutamate 1 receptor in melanoma with a positron emission tomography radioprobe (18) F-FITM.

Int J Cancer 2014 Oct 19;135(8):1852-9. Epub 2014 Mar 19.

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

Oncoimaging using positron emission tomography (PET) with a specific radioprobe would facilitate individualized cancer management. Evidence indicates that ectopically expressed metabotropic glutamate 1 (mGlu1) receptor independently induces melanocyte carcinogenesis, and it is therefore becoming an important target for personalized diagnosis and treatment strategies for melanomas. Here, we report the development of an oncoprotein-based PET imaging platform in melanomas for noninvasive visualization and quantification of mGlu1 with a novel mGlu1-specific radioprobe, 4-(18)F-fluoro-N-[4-[6-(isopropyl amino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ((18)F-FITM). (18)F-FITM shows excellent pharmacokinetics, namely the dense and specific accumulation in mGlu1-positive melanomas versus mGlu1-negative hepatoma and normal tissues. Furthermore, the accumulation levels of radioactivity corresponded to the extent of tumor and to levels of mGlu1 protein expression in melanomas and melanoma metastasis. The (18)F-FITM PET imaging platform, as a noninvasive personalized diagnostic tool, is expected to open a new avenue for defining individualized therapeutic strategies, clinical trials, patient management and understanding mGlu1-triggered oncologic events in melanomas.
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http://dx.doi.org/10.1002/ijc.28842DOI Listing
October 2014

OAT3-mediated extrusion of the 99mTc-ECD metabolite in the mouse brain.

J Cereb Blood Flow Metab 2014 Apr 5;34(4):585-8. Epub 2014 Feb 5.

Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

After administration of the (99m)Tc complex with N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester ((99m)Tc-ECD), a brain perfusion imaging agent, the radioactive metabolite is trapped in primate brain, but not in mouse and rat. Here, we investigate the involvement of metabolite extrusion by organic anion transporter 3 (OAT3), which is highly expressed at the blood-brain barrier in mice, in this species difference. The efflux rate of radioactivity in the cerebrum of Oat3(-/-) mice at later phase was 20% of that of control mice. Thus, organic anion transporters in mouse brain would be involved in the low brain retention of radioactivity after (99m)Tc-ECD administration.
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http://dx.doi.org/10.1038/jcbfm.2014.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982094PMC
April 2014

Characterization of a novel acetamidobenzoxazolone-based PET ligand for translocator protein (18 kDa) imaging of neuroinflammation in the brain.

J Neurochem 2014 May 24;129(4):712-20. Epub 2014 Feb 24.

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, India.

We developed the novel positron emission tomography (PET) ligand 2-[5-(4-[(11)C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([(11)C]MBMP) for translocator protein (18 kDa, TSPO) imaging and evaluated its efficacy in ischemic rat brains. [(11)C]MBMP was synthesized by reacting desmethyl precursor (1) with [(11)C]CH3 I in radiochemical purity of ≥ 98% and specific activity of 85 ± 30 GBq/μmol (n = 18) at the end of synthesis. Biodistribution study on mice showed high accumulation of radioactivity in the TSPO-rich organs, e.g., the lungs, heart, kidneys, and adrenal glands. The metabolite analysis in mice brain homogenate showed 80.1 ± 2.7% intact [(11)C]MBMP at 60 min after injection. To determine the specific binding of [(11)C]MBMP with TSPO in the brain, in vitro autoradiography and PET studies were performed in an ischemic rat model. In vitro autoradiography indicated significantly increased binding on the ipsilateral side compared with that on the contralateral side of ischemic rat brains. This result was supported firmly by the contrast of radioactivity between the ipsilateral and contralateral sides in PET images. Displacement experiments with unlabelled MBMP or PK11195 minimized the difference in uptake between the two sides. In summary, [(11)C]MBMP is a potential PET imaging agent for TSPO and, consequently, for the up-regulation of microglia during neuroinflammation.
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http://dx.doi.org/10.1111/jnc.12670DOI Listing
May 2014

Visualization of acute liver damage induced by cycloheximide in rats using PET with [(18)F]FEDAC, a radiotracer for translocator protein (18 kDa).

PLoS One 2014 23;9(1):e86625. Epub 2014 Jan 23.

Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.

Liver damage induced by drug toxicity is an important concern for both medical doctors and patients. The aim of this study was to noninvasively visualize acute liver damage using positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([(18)F]FEDAC), a radiotracer specific for translocator protein (18 kDa, TSPO) as a biomarker for inflammation, and to determine cellular sources enriching TSPO expression in the liver. A mild acute liver damage model was prepared by a single intraperitoneal injection of cycloheximide (CHX) into rats. Treatment with CHX induced apoptosis and necrotic changes in hepatocytes with slight neutrophil infiltration. The uptake of radioactivity in the rat livers was measured with PET after injection of [(18)F]FEDAC. The uptake of [(18)F]FEDAC increased in livers damaged from treatment with CHX compared to the controls. Presence of TSPO was examined in the liver tissue using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical assays. mRNA expression of TSPO was elevated in the damaged livers compared to the controls, and the level was correlated with the [(18)F]FEDAC uptake and severity of damage. TSPO expression in the damaged liver sections was mainly found in macrophages (Kupffer cells) and neutrophils, but not in hepatocytes. The elevation of TSPO mRNA expression was derived from the increase of the number of macrophages with TSPO and neutrophils with TSPO in damaged livers. From this study we considered that PET imaging with [(18)F]FEDAC represented the mild liver damage through the enhanced TSPO signal in inflammatory cells. We conclude that this method may be a useful tool for diagnosis in early stage of acute liver damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3900578PMC
September 2014
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