Room Temperature Ferromagnetic Semiconductor Rutile Ti1-xCoxO2-\delta Epitaxial Thin Films Grown by Sputtering Method

Room temperature ferromagnetic semiconductor rutile Ti1-xCoxO2-\delta (101) epitaxial thin films were grown on r-sapphire substrates by a dc sputtering method. Ferromagnetic magnetization, magnetic circular dichroism, and anomalous Hall effect were clearly observed at room temperature in sputter-grown films for the first time. The magnetization value is nearly as large as 3\mu B/Co that is consistent with the high spin state Co2+ in this compound recently established by spectroscopic methods. Consequently, its originally large magneto-optical response is further enhanced.Comment: 15 pages, 4 figure

Synthesis and evaluation of novel positron emission tomography probe for metabotropic glutamate receptor 5

The novel highly potent biologically stable metabotropic glutamate receptor 5 (mGlu5) selective positron emission tomography (PET) probes, [11C]-3-fluoro-5-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile ([11C]FPTB) and [11C]-3-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile ([11C]PTB), have been developed using Pd-mediated [11C]cyanation of 2-(2-(3-bromo-5-fluorophenyl)-2H-tetrazol-5-yl)pyridine (Br-FPTB) or 2-(2-(3-bromophenyl)-2H-tetrazol-5-yl)pyridine (Br-PTB). The elaboration of the reaction conditions and evaluation of these 11C-labeled probes (([11C]FPTB) and ([11C]PTB)) will be discussed.WMIC2018(World Molecular Imaging Congress)でのポスター発

Synthesis of [11C]perampanel via CuI-mediated 11C-cyanation and its preliminary in vivo evaluation in mice

Abstract: The introduction of 11C-labelled nitrile group to the organic compounds is one of the most attractive way for the synthesis of many types of 11C-labelled compounds such as 11C-carboxylic acids, 11C-esters, 11C-amides, 11C-tetrazoles, and so on. The most traditional way for the introduction of nitrile group to organic molecule is Rosenmund-von Brown reaction using arylhalide (iodide or bromide) and CuCN. However, introduction of 11C-nitrile group with this method is little bit complicated. Generally, a preparation of Cu11CN is conducted with 11C-anmonium cianide gas and the mixture of freshly prepared solution of sodium metabisulfate and copper(II) sulfate,[1] Thus, we have explored simpler 11C-nitrile group introduction method with Rosenmund-von Brown type reaction. Here we report the CuI-mediated 11C-cyanation of (hetero)aryl bromides and its application for synthesis of [11C]perampanel. And also preliminary in vivo evaluation in mice of [11C]perampanel was performed. Introduction:Perampanel (2-(2-oxo-1-phenyl-5-pyridin-2-yl1,2-dihydropyridin-3-yl)benzonitrile, trade name Fycompa) is a highly selective noncompetitive AMPA receptor antagonist developed by Eisai for treatment of epileptic seizures. Perampanel is currently approved in over 55 countries including the USA, Europe, Russia and Japan. Recently, the prevention of the progression of amyotrophic lateral sclerosis (ALS) by treatment of perampanel is also reported. So far, in order to elucidate the mechanism of perampanel, radiolabelled [3H]perampanel has been synthesized.[2] [11C]perampanel has also synthesized by using of Pd(0)- or Cu(II)-mediated 11C-cyanation methods, however, in vivo PET imaging of this probe has not reported, so far.[3, 4] Thus, we report here the synthesis of [11C]perampanel by using of CuI-mediated 11C-cyanation and its preliminary in vivo evaluation in mice. Methods & Results:Authentic sample and bromophenyl precursor were prepared by according to the literature method as shown in Scheme.[4] The [11C]NH4CN, which was prepared from [11C]CO2, was reacted with bromophenyl precursor in the presence of CuI in DMF at 180 °C for 5 min to give corresponding [11C]perampanel with a decay-corrected isolated radiochemical yield (RCY) of 17±5%, molar activity of 27±19 GBq/mmol and radiochemical purity ≥ 98% with a total synthesis time of 33-36 min. The preliminary bio-distribution evaluation in normal mice was performed. PET study of [11C]perampanel showed high uptake in the intestine (SUV > 2) , liver (SUV > 1.6) , galbladder (SUV > 1.6) and bladder (SUV > 1.2) and low brain uptake (SUV < 0.4) at 30 min time point. References:1. N. Oi, M. Tokunaga, M. Suzuki, Y. Nagai, Y. Nakatani, N. Yamamoto, J. Maeda, T. Minamimoto, M.-R. Zhang, T. Suhara, M. Higuchi, J. Med. Chem. 2015, 58, 8444-8462.2. T. Hanada, Y. Hashizume, N. Tokuhara, O. Takenaka, N. Kohmura, A. Ogasawara, S. Hatakeyama, M. Ohgoh, M. Ueno, Y. Nishizawa, Epilepsia 2011, 52, 1331-1340.3. Lee, H. G.; Milner, P. J.; Placzek, M. S.; Buchwald, S. L.; Hooker, J. M. J Am Chem Soc. 2015,137, 648-651.4. K. J. Makaravage, X. Shao, A. F. Brooks, L. Yang, M. S. Sanford, P. J. H. Scott, Org. Lett., 2018, 20, 1530.WMIC2019でのポスター発

First Quantum Imaging of Metabotropic Glutamate Receptor Subtype 1 in Parkinson’s Disease Rats Using A Novel PET Ligand [11C]ITDM

Parkinson’s disease (PD) is a prevalent degenerative disorder affecting the central nervous system (CNS) that is primarily characterized by resting tremor and movement deficits. Metabotropic glutamate receptor subtype 1 (mGluR1) is an important target for investigation in several CNS disorders. In the present study, we investigated the in vivo role of mGluR1 in chronic PD pathology by performing longitudinal quantum imaging with positron emission tomography (PET) in PD model (PD-Tg) rats. PD-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 availability of [11C]ITDM, a selective PET ligand for mGluR1, temporarily increased prior to PD symptom onset, and dramatically decreased afterwards with age. Moreover, the dynamic changes in striatal availability of [11C]ITDM with mGluR1 also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in [11C]ITDM availability were correlated with decreases in availability of [18F]FE-PE2I, a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated by the quantum imaging technology for the first time that dynamic changes occur in mGluR1, which accompany pathological progression in a PD animal model.QST第1回国際シンポジウム『量子生命科学　-Quantum Life Science-

Scandium triflate-catalyzed N-[18F]Fluoroalkylation of aryl- or heteroaryl-amines with [18F]epifluorohydrin under mild condi-tions

Scandium triflate-catalyzed N-[18F]fluoroalkylation of aryl- or heteroaryl-amines with [18F]epifluorohydrin ([18F]2) was investigated. This reaction is mild and provides one-step access to N-[18F]fluoroalkylated aryl- or heteroaryl-amines, which are used for positron emission tomography imaging. Use of 2,2,2-trifluoroethanol as a cosolvent improved the re-action efficiency. The use of (S)- or (R)-[18F]2 produced the corresponding enantiomeric N-[18F]fluoroalkylated anilines

Radiosynthesis and evaluation of a negative allosteric modulator for the PET imaging of metabotropic glutamate receptor 2 in rat brain

ObjectivesMetabotropic glutamate receptor 2 (mGluR2) is related to a wide variety of brain functions. For this reason, mGluR2 has been appointed as a potential therapeutic target for several neuropsychiatric disorders such as anxiety, schizophrenia, and addiction. So far, several PET tracers targeting mGluR2 have been developed, some of which underwent preclinical imaging in animal studies, but no reliable radiotracer was used for clinical imaging of mGluR2 in human brain. In this study, we aimed to develop a new useful radiotracer for the visualization of mGluR2 in the brain. We established 4‐(2‐fluoro‐4‐methoxyphenyl)‐5‐((2‐methylpyridin‐4‐yl)methoxy)picolinamide (1) as a candidate for mGluR2. Compound 1, an analog of VU6001192,1 is a potent negative allosteric modulator (NAM) and showed high binding affinity for mGluR2 (IC50 = 26nM) than VU6001192 and high brain penetration. Moreover, 1 showed a suitable lipophilicity (cLogD = 3.12). Herein, we performed the chemical syntheses of unlabeled 1 and desmethyl phenol precursor, the radiosynthesis of [11C]1, and the in vitro and vivo specific binding studies in the rodent brain using autoradiography and PET. We also synthesized [11C]VU6001192 and compared its potentials as a PET tracer with [11C]1. Methods[11C]1 and [11C]VU6001192 were synthesized by the reaction of their corresponding desmethy precursors with [11C]methyl iodide. The distribution of radioactivity in mice was measured at different time points after injection of radiotracer. In vitro autoradiography, PET scan, and metabolite analysis were performed on rat brains. Results[11C]1 (7.4 ± 2.8 GBq; n = 8) and [11C]VU6001192 (3.2 ± 1.5 GBq; n = 5) were obtained from [11C]CO2 of 20–22 GBq with >98% radiochemical purity and 70–112 GBq/μmol molar activity. In vitro autoradiography showed that the distribution pattern of [11C]1 radioactivity was heterogeneous with high expression in the cerebral cortex, striatum, hippocampus, and cerebellum. This distribution pattern was consistent with the distribution of mGluR2 in the rat brain. The radioactivity was significantly reduced by self‐ or MNI‐137 (a mGluR2 NAM) blocking. In the mouse brain, the initial uptake of [11C]1 was 1.1%ID/g at 1 min. PET study showed that the uptake of radioactivity peaked at 2 min with a SUV of 0.72 in the cerebral cortex and rapidly decreased afterwards. Self‐blocking with 1 produced a fairly uniform distribution of radioactivity in all brain regions. The PET results suggest that a certain level of in vivo specific binding of [11C]1 could be found in the rat brain. The whole brain uptake increased 74% in Pgp/BCRP‐KO mice, compared to that in wild‐type mice (calculated from the area under curve). Metabolite analysis showed most radioactivity in the brain represented the unchanged [11C]1. On the other hand, PET with [11C]VU6001192 showed a very low brain uptake (SUV < 0.3). ConclusionIn this study, we have synthesized [11C]1 as a new PET tracer with good radiochemical yield, high radiochemical purity, and high molar activity. While [11C]1 has limited potential as a PET tracer for the imaging of brain mGluR2, it can be used to develop new radiotracers with improved in vitro profiles and in vivo behaviors. REFERENCEBollinger K. A., Felts A. S., Brassard C. J., et al. ACS Med. Chem. Lett. 2017, 8, 919–924.ISRS201