ヒト前立腺癌におけるAnti-18F-FACBC (Trans-1-アミノ-3-18F-フルオロシクロブタンカルボン酸) の推定輸送機構と細胞内運命

取得学位 : 博士（保健学）, 学位授与番号 : 医博甲第2188号 , 学位授与年月日 : 平成23年3月22日, 学位授与大学 : 金沢大学, 審査結果の報告日 : 平成23年2月18

Monitoring of Crystallization Process in Solution-Processed Pentacene Thin Films by Chemical Conversion Reactions

Solution-processable organic semiconductors having bulky substituent groups on the π-conjugated skeleton are rapidly gaining attention for their potential applications to large-area electronics. While the substituent groups contribute to the good solubility in organic solvents, they give rise to hopping sites in a thin film, affecting adversely the charge-carrier transport. As an alternative material, a solvent-soluble precursor compound with thermally cleavable functional groups is promising, which can be converted by heat treatment into a thin film to generate the desired material consisting solely of conjugated systems. This precursor approach is practically applied to various thin-film-based devices. The overall process of the thin film growth, however, remains unrevealed. In the present study, solution-processed pentacene thin films are prepared from a thermally convertible precursor, and the structural evolution during the chemical conversion reaction has been revealed by a combination of cutting-edge analytical tools of two-dimensional X-ray diffraction (2D-GIXD) and p-polarized multiple-angle incidence resolution spectrometry (pMAIRS). The highlight is that pentacene is crystallized in a stepwise manner in the thermally converted films, which is substantially different from a typical growth process. In addition, influences of the oxidation reaction of pentacene on the molecular arrangement are also discussed quantitatively. This study provides a fundamental schematic of thin films grown by the precursor method

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro

[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97–230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters

Assessment of Amino Acid/Drug Transporters for Renal Transport of [18F]Fluciclovine (anti-[18F]FACBC) in Vitro

[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97–230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters

Image-forming detectors to observe fine spatial distributions of auroral X-rays

Observations of fine auroral X-ray images at balloon altitude are important for studies of acceleration and precipitation mechanisms of energetic particles in the magnetosphere. Balloon-borne auroral X-ray image-forming detectors with some angular resolution are proposed to observe spatial distributions of auroral X-ray sources, as fine as possible and also as a function of time. Two systems of image-forming detectors are being developed. One system consists of two sets of Nal (Tl) scintillation detectors with very thin scintillators. The first set has a collimator with multi-pinholes, giving an angular resolution of 5°. The second has a collimator with a single larger pinhole, and it eliminates the redundant images unavoidable in the multi-pinhole type of detector. The incident position of an X-ray on the thin scintillator is determined by using the signals from four photomultiplier tubes attached to the scintillator. The other system is constructed with the Nal (Tl) scintillator viewed by a microchannel plate photomultiplier tube (MCP PMT) through a Fresnel lens. The pinhole aperture of the collimator is selected according to the auroral X-ray intensity, giving an angular resolution of 2°, 5°or 10°. It is expected that auroral X-ray images can be observed with an angular resolution of 5°and with a time resolution of 1s, for the moderate activity of an auroral X-ray burst

Transport mechanism and affinity of [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]MAG3) on the apical membrane of renal proximal tubule cells

Technetium-99m-labeled mercaptoacetyltriglycine ([99mTc]MAG3) is widely used for evaluation of transplanted kidneys, diagnosis of tubular necrosis, and scintigraphic studies of tubular function. [99mTc]MAG3 is a substrate for organic anion transporter (OAT)1 and OAT3 on the basolateral membrane side for renal secretion. We investigated the transport mechanism and affinity of [99mTc]MAG3 on the apical membrane of renal proximal tubule cells for renal secretion. Adenosine triphosphate-binding cassette (ABC) transporters for renal secretion of [99mTc]MAG3 were examined using ABC transporter vesicles expressing multiple drug resistance 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP)2, and MRP4. MK-571, a MRP inhibitor, was applied to measure the Km and Vmax of MRP2 and MRP4 in a vesicle transport assay. Single photon emission computed tomography (SPECT) was performed in normal rats and MRP2-deficient Eisai hyperbilirubinuria rats (EHBR) using [99mTc]MAG3 with and without MK-571. [99mTc]MAG3 uptake in adenosine triphosphate was significantly higher than that in adenosine monophosphate in vesicles that highly expressed MRP2 and MRP4. The affinity of [99mTc]MAG3 for MRP4 was higher than that for MRP2. Renal secretion via MRP2 and MRP4 was identified by comparing normal and EHBR rats with and without MK-571 on SPECT. [99mTc]MAG3 is transported via MRP2 and MRP4 on the apical membrane of renal proximal tubule cells. The affinity of MRP4 is higher than that of MRP2