Publications by authors named "Ming-Rong Zhang"

308 Publications

Synthesis of no-carrier-added [Pt]cisplatin from a cyclotron produced PtCl complex.

Sci Rep 2021 Apr 14;11(1):8140. Epub 2021 Apr 14.

Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science (iQMS), National Institutes for Quantum and Radiological Science and Technology (QST), 4-9-1 Anagawa, Inage-ku, Chiba, 263-8555, Japan.

We developed a novel method for production of no-carrier-added (n.c.a.) [Pt]PtCl from an Ir target material, and then synthesized n.c.a. [*Pt]cis-[PtCl(NH)] ([*Pt]cisplatin) from [*Pt]PtCl. [*Pt]PtCl was prepared as a synthetic precursor of n.c.a. *Pt complex by a combination of resin extraction and anion-exchange chromatography after the selective reduction of IrCl with ascorbic acid. The ligand-substitution reaction of Cl with NH was promoted by treating n.c.a. [*Pt]PtCl with excess NH and heating the reaction mixture, and n.c.a. [*Pt]cisplatin was successfully produced without employing precipitation routes. After this treatment, [*Pt]cisplatin was isolated through preparative HPLC with a radiochemical purity of 99 + % at the end of synthesis (EOS).
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http://dx.doi.org/10.1038/s41598-021-87576-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046966PMC
April 2021

PET imaging of colony-stimulating factor 1 receptor: A head-to-head comparison of a novel radioligand, C-GW2580, and C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey.

J Cereb Blood Flow Metab 2021 Mar 24:271678X211004146. Epub 2021 Mar 24.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Colony-stimulating factor 1 receptor (CSF1R) is a specific biomarker for microglia. In this study, we developed a novel PET radioligand for CSF1R, C-GW2580, and compared it to a reported CSF1R tracer, C-CPPC, in mouse models of acute and chronic neuroinflammation and a rhesus monkey. Dynamic C-GW2580- and C-CPPC-PET images were quantified by reference tissue-based models and standardized uptake value ratio. Both tracers exhibited increased uptake in the lesioned striata of lipopolysaccharide-injected mice and in the forebrains of -knock-in mice, spatially in agreement with an increased 18-kDa translocator protein radioligand retention. Moreover, C-GW2580 captured changes in CSF1R availability more sensitively than C-CPPC, with a larger dynamic range and a smaller inter-individual variability, in these model animals. PET imaging of CSF1R in a rhesus monkey displayed moderate-to-high tracer retention in the brain at baseline. Homologous blocker (i. e. unlabeled tracer) treatment reduced the uptake of C-GW2580 by ∼30% in all examined brain regions except for centrum semi-ovale white matter, but did not affect the retention of C-CPPC. In summary, our results demonstrated that C-GW2580-PET captured inflammatory microgliosis in the mouse brain with higher sensitivity than a reported radioligand, and displayed saturable binding in the monkey brain, potentially providing an imaging-based quantitative biomarker for reactive microgliosis.
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http://dx.doi.org/10.1177/0271678X211004146DOI Listing
March 2021

Synthesis and preclinical evaluation of [C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain.

Eur J Nucl Med Mol Imaging 2021 Mar 5. Epub 2021 Mar 5.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.

Purpose: Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.

Methods: [C]MTP38 was radiosynthesized by C-cyanation of a bromo precursor with [C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (V). The non-displaceable binding potential (BP) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BP.

Results: [C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated V values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm, respectively. The cerebellar V value was unchanged by pretreatment with unlabeled MTP38. Striatal BP was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill's sigmoidal function.

Conclusion: We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.
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http://dx.doi.org/10.1007/s00259-021-05269-4DOI Listing
March 2021

Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging.

Mol Pharm 2021 04 1;18(4):1507-1529. Epub 2021 Mar 1.

Department of Chemistry, Babasaheb Bhimrao Ambedkar University, (A Central University), Lucknow, Uttar Pradesh 226025, India.

Positron emission tomography (PET) imaging of the translocator 18 kDa protein (TSPO) with radioligands has become an effective means of research in peripheral inflammatory conditions that occur in many diseases and cancers. The peripheral sterile inflammatory diseases (PSIDs) are associated with a diverse group of disorders that comprises numerous enduring insults including the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system. TSPO has recently been introduced as a potential biomarker for peripheral sterile inflammatory diseases (PSIDs). The major critical issue related to PSIDs is its timely characterization and localization of inflammatory for proper therapy of patients. As an alternative to metabolic imaging, protein imaging expressed on immune cells after activation is of great importance. The five transmembrane domain translocator protein-18 kDa (TSPO) is upregulated on the mitochondrial cell surface of macrophages during inflammation, serving as a potential ligand for PET tracers. Additionally, the overexpressed TSPO protein has been positively correlated with various tumor malignancies. In view of the association of escalated TSPO expression in both disease conditions, it is an immensely important biomarker for PET imaging in oncology and PSIDs. In this review, we summarize the most outstanding advances on TSPO-targeted PSIDs and cancer in the development of TSPO ligands as a potential diagnostic tool, specifically discussing the last five years.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00002DOI Listing
April 2021

Distinct microglial response against Alzheimer's amyloid and tau pathologies characterized by P2Y12 receptor.

Brain Commun 2021 29;3(1):fcab011. Epub 2021 Jan 29.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Microglia are the resident phagocytes of the central nervous system, and microglial activation is considered to play an important role in the pathogenesis of neurodegenerative diseases. Recent studies with single-cell RNA analysis of CNS cells in Alzheimer's disease and diverse other neurodegenerative conditions revealed that the transition from homeostatic microglia to disease-associated microglia was defined by changes of gene expression levels, including down-regulation of the P2Y12 receptor gene (). However, it is yet to be clarified in Alzheimer's disease brains whether and when this down-regulation occurs in response to amyloid-β and tau depositions, which are core pathological processes in the disease etiology. To further evaluate the significance of P2Y12 receptor alterations in the neurodegenerative pathway of Alzheimer's disease and allied disorders, we generated an anti-P2Y12 receptor antibody and examined P2Y12 receptor expressions in the brains of humans and model mice bearing amyloid-β and tau pathologies. We observed that the brains of both Alzheimer's disease and non-Alzheimer's disease tauopathy patients and tauopathy model mice (rTg4510 and PS19 mouse lines) displayed declined microglial P2Y12 receptor levels in regions enriched with tau inclusions, despite an increase in the total microglial population. Notably, diminution of microglial immunoreactivity with P2Y12 receptor was noticeable prior to massive accumulations of phosphorylated tau aggregates and neurodegeneration in rTg4510 mouse brains, despite a progressive increase of total microglial population. On the other hand, Iba1-positive microglia encompassing compact and dense-cored amyloid-β plaques expressed P2Y12 receptor at varying levels in amyloid precursor protein (APP) mouse models (APP23 and mice). By contrast, neuritic plaques in Alzheimer's disease brains were associated with P2Y12 receptor-negative microglia. These data suggest that the down-regulation of microglia P2Y12 receptor, which is characteristic of disease-associated microglia, is intimately associated with tau rather than amyloid-β pathologies from an early stage and could be a sensitive index for neuroinflammatory responses to Alzheimer's disease-related neurodegenerative processes.
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http://dx.doi.org/10.1093/braincomms/fcab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901060PMC
January 2021

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.

Acta Pharm Sin B 2021 Feb 25;11(2):373-393. Epub 2020 Aug 25.

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

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
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http://dx.doi.org/10.1016/j.apsb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893127PMC
February 2021

Design, Synthesis, and Biological Evaluation of Novel Fluorescent Probes Targeting the 18-kDa Translocator Protein.

ChemMedChem 2021 Feb 25. Epub 2021 Feb 25.

School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, NSW, 2522, Australia.

A series of fluorescent probes from the 6-chloro-2-phenylimidazo[1,2-a]pyridine-3-yl acetamides ligands featuring the 7-nitro-2-oxa-1,3-diazol-4-yl (NBD) moiety has been synthesized and biologically evaluated for their fluorescence properties and for their binding affinity to the 18-kDa translocator protein (TSPO). Spectroscopic studies including UV/Vis absorption and fluorescence measurements showed that the synthesized fluorescent probes exhibit favorable spectroscopic properties, especially in nonpolar environments. In vitro fluorescence staining in brain sections from lipopolysaccharide (LPS)-injected mice revealed partial colocalization of the probes with the TSPO. The TSPO binding affinity of the probes was measured on crude mitochondrial fractions separated from rat brain homogenates in a [ C]PK11195 radioligand binding assay. All the new fluorescent probes demonstrated moderate to high binding affinity to the TSPO, with affinity (K ) values ranging from 0.58 nM to 3.28 μM. Taking these data together, we propose that the new fluorescent probes could be used to visualize the TSPO.
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http://dx.doi.org/10.1002/cmdc.202000984DOI Listing
February 2021

A first-in-human study of C-MTP38, a novel PET ligand for phosphodiesterase 7.

Eur J Nucl Med Mol Imaging 2021 Feb 10. Epub 2021 Feb 10.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.

Purpose: Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.

Methods: Seven healthy males underwent a 90-min PET scan after injection of C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (Vs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTM) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.

Results: PET images with C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. V values were robustly estimated by two-tissue compartment model analysis (mean V = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTM and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTM and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of C-MTP38-PET.

Conclusion: We have provided the first demonstration of PET visualization of PDE7 in human brains. C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.
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http://dx.doi.org/10.1007/s00259-021-05235-0DOI Listing
February 2021

Detection of Alzheimer's disease-related neuroinflammation by a PET ligand selective for glial versus vascular translocator protein.

J Cereb Blood Flow Metab 2021 Feb 8:271678X21992457. Epub 2021 Feb 8.

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

A substantial and constitutive expression of translocator protein (TSPO) in cerebral blood vessels hampers the sensitive detection of neuroinflammation characterized by greatly induced TSPO expression in activated glia. Here, we conducted in vivo positron emission tomography (PET) and in vitro autoradiographic imaging of normal and TSPO-deficient mouse brains to compare the binding properties of F-FEBMP, a relatively novel TSPO radioligand developed for human studies based on its insensitivity to a common polymorphism, with C-PK11195, as well as other commonly used TSPO radioligands including C-PBR28, C-Ac5216 and F-FEDAA1106. TSPO in cerebral vessels of normal mice was found to provide a major binding site for C-PK11195, C-PBR28 and F-FEDAA1106, in contrast to no overt specific binding of F-FEBMP and C-Ac5216 to this vascular component. In addition, F-FEBMP yielded PET images of microglial TSPO with a higher contrast than C-PK11195 in a tau transgenic mouse modeling Alzheimer's disease (AD) and allied neurodegenerative tauopathies. Moreover, TSPO expression examined by immunoblotting was significantly increased in AD brains compared with healthy controls, and was well correlated with the autoradiographic binding of F-FEBMP but not C-PK11195. Our findings support the potential advantage of comparatively glial TSPO-selective radioligands such as F-FEBMP for PET imaging of inflammatory glial cells.
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http://dx.doi.org/10.1177/0271678X21992457DOI Listing
February 2021

Radiosynthesis and evaluation of 4-(6-[F]Fluoro-4-(5-isopropoxy-1-indazol-3-yl)pyridin-2-yl)morpholine as a novel radiotracer candidate targeting leucine-rich repeat kinase 2.

RSC Med Chem 2020 Jun 19;11(6):676-684. Epub 2020 May 19.

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

Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity in the brain are associated with Parkinson's disease. Here, we synthesized a novel compound 4-(6-fluoro-4-(5-isopropoxy-1-indazol-3-yl)pyridin-2-yl)morpholine (FIPM) and labeled it with fluorine-18 (F), to develop a positron emission tomography (PET) tracer for visualization of LRRK2 in the brain. FIPM showed high binding affinity for LRRK2 (IC = 8.0 nM). [F]FIPM was prepared in 5% radiochemical yield ( = 5), by inserting F into a pyridine ring, followed by removal of the protecting group. After HPLC separation and formulation, [F]FIPM was acquired with >97% radiochemical purity and 103-300 GBq μmol of molar activity at the end of radiosynthesis. Biodistribution and small-animal PET studies in mice indicated a low specific binding of [F]FIPM. While [F]FIPM presented limited potential as an PET tracer for LRRK2, we suggested that it can be used as a lead compound for developing new radiotracers with improved brain properties.
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http://dx.doi.org/10.1039/c9md00590kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649847PMC
June 2020

Biodistribution and radiation dosimetry of the positron emission tomography probe for AMPA receptor, [C]K-2, in healthy human subjects.

Sci Rep 2021 Jan 15;11(1):1598. Epub 2021 Jan 15.

Department of Physiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

[C]K-2, a radiotracer exhibiting high affinity and selectivity for α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), is suitable for the quantification of AMPARs in living human brains and potentially useful in the identification of epileptogenic foci in patients. This study aimed to estimate the radiation doses of [C]K-2 in various organs and calculate the effective dose after injection of [C]K-2 in healthy human subjects. Twelve healthy male subjects were registered and divided into two groups (370 or 555 MBq of [C]K-2), followed by 2 h whole-body scans. We estimated the radiation dose of each organ and then calculated the effective dose for each subject. The highest uptake of [C]K-2 was observed in the liver, while the brain also showed relatively high uptake. The urinary bladder exhibited the highest radiation dose. The kidneys and liver also showed high radiation doses after [C]K-2 injections. The effective dose of [C]K-2 ranged from 5.0 to 5.2 μSv/MBq. Our findings suggest that [C]K-2 is safe in terms of the radiation dose and adverse effects. The injection of 370-555 MBq (10 to 15 mCi) for PET studies using this radiotracer is applicable in healthy human subjects and enables serial PET scans in a single subject.
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http://dx.doi.org/10.1038/s41598-021-81002-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810729PMC
January 2021

Radiosynthesis of F-fluoroethylated tracers via a simplified one-pot F-fluoroethylation method using [F]fluoroethyl tosylate.

Appl Radiat Isot 2021 Mar 26;169:109571. Epub 2020 Dec 26.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-855, Japan.

Recently, a straightforward one-pot method for F-fluoroethylation without azeotropic drying of cyclotron-produced [F]F was developed. In this study, we have attempted to simplify the automated radiosynthesis of two [F]fluoroethylated tracers, [F]FEDAC and [F]FET, using a desmethyl labeling precursor and [F]fluoroethyl tosylate, based on the above-mentioned method. The radiochemical yields of [F]FEDAC and [F]FET were 26 ± 3.7% (n = 5) and 14 ± 2.2% (n = 4), respectively, based on total [F]F at the end of irradiation.
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http://dx.doi.org/10.1016/j.apradiso.2020.109571DOI Listing
March 2021

Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development.

J Med Chem 2021 01 30;64(1):123-149. Epub 2020 Dec 30.

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

The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877880PMC
January 2021

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies.

Neuron 2021 01 29;109(1):42-58.e8. Epub 2020 Oct 29.

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

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.
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http://dx.doi.org/10.1016/j.neuron.2020.09.042DOI Listing
January 2021

Radiosynthesis and quality control testing of the tau imaging positron emission tomography tracer [ F]PM-PBB3 for clinical applications.

J Labelled Comp Radiopharm 2021 Mar 7;64(3):109-119. Epub 2020 Nov 7.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Recently, we produced C-labeled 2-((1E,3E)-4-(6-(methylamino)pyridin-3-yl)buta-1,3-dienyl)benzo[d]thiazol-6-ol ([ C]PBB3) as a clinically useful positron emission tomography (PET) tracer for in vivo imaging of tau pathologies in the human brain. To overcome the limitations (i.e., rapid in vivo metabolism and short half-life) of [ C]PBB3, we further synthesized F-labeled 1-fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([ F]PM-PBB3). [ F]PM-PBB3 is also a useful tau PET tracer for imaging tau pathologies. In this study, we developed a routine radiosynthesis and quality control testing of [ F]PM-PBB3 for clinical applications. [ F]PM-PBB3 was synthesized by direct F-fluorination of the tosylated derivative, followed by removal of the protecting group. [ F]PM-PBB3 was obtained with sufficient radioactivity (25 ± 6.0% of the nondecay-corrected radiochemical yield at the end of synthesis, EOS), radiochemical purity (98 ± 0.6%), and molar activity (350 ± 94 GBq/μmol at EOS; n = 53). Moreover, [ F]PM-PBB3 consistently retained >95% of radiochemical purity for 60 min without undergoing photoisomerization using a new UV-cutoff light (yellow light) fixed in the hot cell to monitor the synthesis. All the results of the quality control testing for the [ F]PM-PBB3 injection complied with our in-house quality control and quality assurance specifications. We have accomplished >200 production runs of [ F]PM-PBB3 in our facility for various research purposes.
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http://dx.doi.org/10.1002/jlcr.3890DOI Listing
March 2021

Smart Titanium Coating Composed of Antibiotic Conjugated Peptides as an Infection-Responsive Antibacterial Agent.

Macromol Biosci 2021 01 13;21(1):e2000194. Epub 2020 Oct 13.

Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, 100029, P. R. China.

Antibacterial coating is rapidly emerging as a pivotal strategy for mitigating spread of bacterial pathogens. However, many challenges still need to be overcome in order to develop a smart coating that can achieve on-demand antibacterial effects. In this study, a Staphylococcus aureus (S. aureus) sensitive peptide sequence is designed, and an antibiotic is then conjugated with this tailor-made peptide. The antibiotic-peptide conjugate is then linked to the surface of a titanium implant, where the peptide can be recognized and cleaved by an enzyme secreted by S. aureus. This allows for the release of antibiotics in the presence of S. aureus, thus achieving delivery of an antibacterial specifically when an infection occurs.
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http://dx.doi.org/10.1002/mabi.202000194DOI Listing
January 2021

Synthesis and preliminary studies of C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2.

Theranostics 2020 14;10(24):11178-11196. Epub 2020 Sep 14.

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

Selective modulation of metabotropic glutamate receptor 2 (mGlu) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu using positron emission tomography (PET) would allow for quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu. A focused small molecule library of mGlu NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu NAMs, among which compounds and were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the binding specificity and selectivity of [C] and [C] towards mGlu. binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [C] as most promising PET mGlu PET ligand. mGlu NAMs were synthesized in 14%-20% yields in five steps. NAMs and were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [C] and [C] displayed similar heterogeneous distribution by autoradiography, consistent with mGlu expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [C] demonstrated superior binding specificity compared to [C]. Further radiometabolite analysis of [C] showed excellent stability in the brain. Compound exhibited high affinity and excellent subtype selectivity, which was then evaluated by autoradiography and PET imaging study after labeling with carbon-11. Ligand [C], which we named [C]MG2-1904, demonstrated high brain uptake and excellent / specific binding towards mGlu with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.
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http://dx.doi.org/10.7150/thno.42587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532674PMC
September 2020

Cyclotron production of no carrier added Re radionuclide for theranostic applications.

Appl Radiat Isot 2020 Dec 15;166:109428. Epub 2020 Sep 15.

Centre for Biomedical Physics, School of Healthcare and Medical Sciences, Sunway University, 47500 Bandar Sunway, Selangor, Malaysia, & Department of Physics, University of Malaya, 50603, Kuala Lumpur, Malaysia; Department of Physics, University of Surrey, Guildford, Surrey GU2 7XH, UK.

Re (T = 3.7183 d, E = 346.7 keV, I = 92.59%), a mixed beta and γ-emitter shows great potential for use in theranostic applications. The dominant Re(n,γ) route, via use of a nuclear reactor, provides Re in carrier added form with low specific activity, while cyclotrons offer no carrier-added (NCA) high specific activity production of Re. However, to be able to select the best possible nuclear reaction and to optimize the production route via the use of a cyclotron, information on the excitation function for the reaction of interest as well as for the competing reactions is necessary. Accordingly, we have conducted a detailed study of the excitation functions for W(d, x) reactions in seeking optimized parameters for the NCA production of Re. Noting a discrepancy among the experimental data, we made an evaluation of the available literature, finally selecting optimum parameters for the production of Re via the W(d,2n)Re reaction. These beam parameters were then used for batch production of Re by irradiating an enriched W metallic powder target, followed by a subsequent automated chemical separation process. The preliminary results show 98.1% radionuclidic purity of Re at 8 h subsequent to the End of Bombardment (EOB), offering the potential for use in clinical applications.
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http://dx.doi.org/10.1016/j.apradiso.2020.109428DOI Listing
December 2020

Identification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[C]methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu).

J Med Chem 2020 10 22;63(20):11469-11483. Epub 2020 Sep 22.

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.

Metabotropic glutamate receptor 2 (mGlu) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu, we identified new candidates - that are potent negative allosteric modulators (NAMs) of mGlu. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1-pyrazol-3-yl)methoxy)picolinamide (, also named as [C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound was labeled with positron-emitting carbon-11 (C) to obtain [C] in high radiochemical yield and high molar activity by -[C]methylation of the phenol precursor with [C]CHI. autoradiography with [C] showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [C] indicated specific binding of mGlu in the rat brain. Based on the [C] scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892210PMC
October 2020

3-(Cyclopropylmethyl)-7-((4-(4-[C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2.

Bioorg Med Chem Lett 2020 12 15;30(23):127555. Epub 2020 Sep 15.

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:

Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (CMTP, 1a). [C]CMTP ([C]1a) was synthesized by O-[C]methylation of desmethyl precursor 1b with [C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [C]CO) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [C]1a possessed moderate in vitro specific binding to mGluR2 in the rat brain, with a heterogeneous distribution of radioactive accumulation in the mGluR2-rich brain tissue sections, such as the cerebral cortex and striatum. PET study indicated that [C]1a was able to cross the blood-brain barrier and enter the brain, but had very low specific binding in the rat brain. Further optimization for the chemical structure of 1a is necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain.
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http://dx.doi.org/10.1016/j.bmcl.2020.127555DOI Listing
December 2020

Radiotheranostic Agent Cu-cyclam-RAFT-c(-RGDfK-) for Management of Peritoneal Metastasis in Ovarian Cancer.

Clin Cancer Res 2020 Dec 15;26(23):6230-6241. Epub 2020 Sep 15.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Purpose: Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αβ integrin (αβ) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αβ-positive OCPM mouse models, we studied the theranostic potential of an αβ-specific radiopeptide, Cu-cyclam-RAFT-c(-RGDfK-) (Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.

Experimental Design: αβ-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.

Results: Intraperitoneal administration was an efficient route for targeting Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. Cu-RaftRGD-based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2-17.2 mm). Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.

Conclusions: Collectively, these results demonstrate the all-in-one potential of Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing αβ- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1205DOI Listing
December 2020

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study.

Cereb Cortex 2020 Nov;30(12):6458-6468

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Chiba 263-8555, Japan.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the "attention to detail" subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.
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http://dx.doi.org/10.1093/cercor/bhaa211DOI Listing
November 2020

Synthesis and preliminary evaluation of novel C-labeled GluN2B-selective NMDA receptor negative allosteric modulators.

Acta Pharmacol Sin 2021 Mar 13;42(3):491-498. Epub 2020 Jul 13.

Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.

N-methyl-D-aspartate receptors (NMDARs) play critical roles in the physiological function of the mammalian central nervous system (CNS), including learning, memory, and synaptic plasticity, through modulating excitatory neurotransmission. Attributed to etiopathology of various CNS disorders and neurodegenerative diseases, GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs. Herein, we report the synthesis and preclinical evaluation of two C-labeled GluN2B-selective negative allosteric modulators (NAMs) containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography (PET) imaging. Two PET ligands, namely [C]31 and [C]37 (also called N2B-1810 and N2B-1903, respectively) were labeled with [C]CHI in good radiochemical yields (decay-corrected 28% and 32% relative to starting [C]CO, respectively), high radiochemical purity (>99%) and high molar activity (>74 GBq/μmol). In particular, PET ligand [C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies. However, because in vivo PET imaging studies showed limited brain uptake of [C]31 (up to 0.5 SUV), further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.
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http://dx.doi.org/10.1038/s41401-020-0456-9DOI Listing
March 2021

Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.

Nat Neurosci 2020 09 6;23(9):1157-1167. Epub 2020 Jul 6.

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.
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http://dx.doi.org/10.1038/s41593-020-0661-3DOI Listing
September 2020

Synthesis and preliminary evaluation of 4-hydroxy-6-(3-[C]methoxyphenethyl)pyridazin-3(2H)-one, a C-labeled d-amino acid oxidase (DAAO) inhibitor for PET imaging.

Bioorg Med Chem Lett 2020 08 9;30(16):127326. Epub 2020 Jun 9.

Department of Radiology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, United States. Electronic address:

Selective DAAO inhibitors have demonstrated promising therapeutic effects in clinical studies, including clinically alleviating symptoms of schizophrenic patients and ameliorating cognitive function in Alzheimer's patients with early phase. Herein we report the synthesis and preliminary evaluation of a C-labeled positron emission tomography ligand based on a DAAO inhibitor, DAO-1903 (8). C-Isotopologue of 8 was prepared in high radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed high in vitro specific binding to DAAO, while in vivo dynamic PET studies demonstrated that [C]8 failed to cross the blood-brain barrier possibly due to moderate brain efflux mechanism. Further chemical scaffold optimization is necessary to overcome limited brain permeability and improve specific binding.
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http://dx.doi.org/10.1016/j.bmcl.2020.127326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363051PMC
August 2020

In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy.

Neurobiol Aging 2020 10 19;94:140-148. Epub 2020 May 19.

Department of Functional Brain Imaging, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. Electronic address:

Damaged mitochondria may be one of the earliest manifestations of Alzheimer's disease. Because oxidative phosphorylation is a primary source of neuronal energy, unlike glycolysis-dependent energy production in inflamed glia, mitochondrial respiration could provide a selective biomarker of neuronal deterioration in Alzheimer's disease. Here we used a recently developed positron emission tomography (PET) probe targeting mitochondrial complex I (MC-I), F-BCPP-EF, to non-invasively visualize mitochondrial abnormalities in the brains of tau transgenic mice (rTg4510). Tauopathy and neuroinflammation were visualized by PET using a tau probe C-PBB3 and a translocator protein probe, F-FEBMP, respectively. A marked reduction in F-BCPP-EF uptake was observed in hippocampal and forebrain regions of tau transgenic mice, colocalizing with regions of tauopathy, neuronal damage, and neuroinflammation. MC-I signals were highly correlated with atrophy assayed by magnetic resonance imaging, but negatively associated with inflammatory signals, indicating that neuronal metabolic signals measured by MC-I PET were robust to inflammatory interference. MC-I may be a useful imaging biomarker to detect neuronal damage and metabolic changes with minimal interference from concomitant glial hypermetabolism.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.05.003DOI Listing
October 2020

Excess tau PET ligand retention in elderly patients with major depressive disorder.

Mol Psychiatry 2020 Jul 1. Epub 2020 Jul 1.

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [C]PBB3, and an Aβ radioligand, [C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.
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http://dx.doi.org/10.1038/s41380-020-0766-9DOI Listing
July 2020

[C]phosgene: Synthesis and application for development of PET radiotracers.

Nucl Med Biol 2021 01 1;92:138-148. Epub 2020 May 1.

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:

Carbon-11-labeled phosgene ([C]phosgene, [C]COCl) is a useful labeling agent that connects two heteroatoms by inserting [C]carbonyl (C=O) function in carbamates, ureas, and carbonates, which are components of biologically important heterocyclic compounds and functional groups in drugs as a linker of fragments with in vivo stability. Development of C-labeled PET tracers has been performed using [C]phosgene as a labeling agent. However, [C]phosgene has not been frequently used for C-labeling because preparation of [C]phosgene required dedicated synthesis apparatus (not commercially available) and had problems in reproducibility and reliability. In our laboratory, an improved method for synthesizing [C]phosgene using a carbon tetrachloride detection tube kit in environmental air analysis and the automated synthesis system for preparing [C]phosgene have been developed in 2009. This apparatus has been used for routine synthesis of C-labeled tracers 1-4 times/week. Using [C]phosgene we have developed and produced many PET radiotracers containing [C]urea and [C]carbamate moieties. In this review, we report the performance of our method for preparing [C]phosgene, including automated synthesis apparatus developed in house, and the application of [C]phosgene for development and production of C-labeled PET tracers.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.04.007DOI Listing
January 2021

Marriage of black phosphorus and Cu as effective photothermal agents for PET-guided combination cancer therapy.

Nat Commun 2020 06 8;11(1):2778. Epub 2020 Jun 8.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 2638555, Japan.

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing Cu, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
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http://dx.doi.org/10.1038/s41467-020-16513-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280494PMC
June 2020

Simultaneous measurements of the molar radioactivity, radiochemical purity and chemical impurity in the [C]choline injection using radio-HPLC with a corona-charged aerosol detector.

Appl Radiat Isot 2020 Aug 27;162:109192. Epub 2020 Apr 27.

Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan.

[C]choline has a weak UV absorption chromophore, and it is challenging to detect less than 1 μg/mL choline using radio-HPLC-UV. In this study, we established an analytical procedure of [C]choline using the radio-HPLC coupled with the corona-charged aerosol detector. As a result, we achieved more than 100 GBq/μmol (over 0.1 μg/mL of choline) of molar radioactivity at the end of synthesis, over 95% of radiochemical purity, and more than 0.1 μg/mL of 2-dimethyoaminoethanol as a chemical impurity.
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http://dx.doi.org/10.1016/j.apradiso.2020.109192DOI Listing
August 2020