K Horiuchi

Kyoto University, Kyoto, Kyoto-fu, Japan

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Publications (72)79.17 Total impact

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    ABSTRACT: 6-Hydrazinopyridine-3-carboxylic acid (HYNIC) constitutes one of the most attractive reagents to prepare (99m)Tc-labeled polypeptides and peptides of various molecular weights in combination with two tricine molecules as coligands. Indeed, (99m)Tc-HYNIC-conjugated IgG showed biodistribution of radioactivity similar to that of (111)In-DTPA-conjugated IgG. However, recent studies indicated significant plasma protein binding when the (99m)Tc labeling procedure was expanded to low molecular weight peptides. In this study, pharmacokinetics of (99m)Tc-HYNIC-conjugated IgG, Fab and RC160 using tricine were compared with their radioiodinated counterparts to evaluate this (99m)Tc-labeling method. In mice, [(99m)Tc](HYNIC-IgG)(tricine)(2) and [(99m)Tc](HYNIC-Fab)(tricine)(2) showed persistent localization of radioactivity in tissues when compared with their (125)I-labeled counterparts. [(99m)Tc](HYNIC-IgG)(tricine)(2) eliminated from the blood at a rate similar to that of (125)I-labeled IgG, while [(99m)Tc](HYNIC-Fab)(tricine)(2) showed significantly slower clearance of the radioactivity than (125)I-labeled Fab. On size-exclusion HPLC analyses, little changes were observed in radiochromatograms after incubation of [(99m)Tc](HYNIC-IgG)(tricine)(2) in murine plasma. However, [(99m)Tc](HYNIC-Fab)(tricine)(2) and [(99m)Tc](HYNIC-RC160)(tricine)(2) demonstrated significant increases in the radioactivity in higher molecular weight fractions in plasma. Formation of higher molecular weight species was reduced when [(99m)Tc](HYNIC-RC160)(tricine)(2) was stabilized with nicotinic acid (NIC) to generate [(99m)Tc](HYNIC-RC160)(tricine)(NIC). [(99m)Tc](HYNIC-RC160)(tricine)(NIC) also demonstrated significantly faster clearance of the radioactivity from the blood than [(99m)Tc](HYNIC-RC160)(tricine)(2). These findings suggested that one of the tricine coligands in (99m)Tc-HYNIC-labeled (poly)peptides would be replaced with plasma proteins to generate higher molecular weight species that exhibit slow blood clearance. In addition, the molecular sizes of parental peptides played an important role in the progression of the exchange reaction of one of the tricine coligands with plasma proteins.
    Nuclear Medicine and Biology 03/2001; 28(2):155-64. · 2.52 Impact Factor
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    ABSTRACT: Works on dithiosemicarbazone (DTS) derivatives radiolabeled with divalent Cu (Cu-62, Cu-64) indicate its potentiality as an ischemic tissue detecting agent. Development of analogous derivatives labeled with the more accessible technetium-99m (Tc) is most desirable. Various synthesized DTS derivatives are radiolabeled with a novel approach, using a macromolecular Sn(II)-complex under an anaerobic condition at pH 3.4-4.5 and stabilization by ascorbate solution at pH 6.7-7.0. Characterization of Tc-DTS derivatives done by various analytical methods (TLC, HPLC, EP, PC) and by in vivo studies in normal mice and in rats myocardial LAD (left anterior descent coronary artery) occlusion model. Among tested DTS, only Tc-ATSE, Tc-ATSM and Tc-ATSM(2) showed distinctive characteristics, with the latter presenting high myocardium uptake in regions of ischemia in LAD rat myocardium model. Potentiality of the Cu-DTS mimetic agent, Tc-ATSM(2) as an ischemia-damaged myocardium agent is discussed.
    Nuclear Medicine and Biology 06/2000; 27(4):391-9. · 2.52 Impact Factor
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    ABSTRACT: Works on dithiosemicarbazone (DTS) derivatives radiolabeled with divalent Cu (Cu-62, Cu-64) indicate its potentiality as an ischemic tissue detecting agent. Development of analogous derivatives labeled with the more accessible technetium-99m (Tc) is most desirable. Various synthesized DTS derivatives are radiolabeled with a novel approach, using a macromolecular Sn(II)-complex under an anaerobic condition at pH 3.4–4.5 and stabilization by ascorbate solution at pH 6.7–7.0. Characterization of Tc-DTS derivatives done by various analytical methods (TLC, HPLC, EP, PC) and by in vivo studies in normal mice and in rats myocardial LAD (left anterior descent coronary artery) occlusion model. Among tested DTS, only Tc-ATSE, Tc-ATSM and Tc-ATSM2 showed distinctive characteristics, with the latter presenting high myocardium uptake in regions of ischemia in LAD rat myocardium model. Potentiality of the Cu-DTS mimetic agent, Tc-ATSM2 as an ischemia-damaged myocardium agent is discussed.
    Nuclear Medicine and Biology 01/2000; 27(4):391-399. · 2.52 Impact Factor
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    ABSTRACT: Recent development of a variety of thiol-free chelating agents has facilitated the design of 99mTc-labeled somatostatin analogs suitable for receptor imaging of somatostatin-positive tumors. However, it remains ambiguous whether the disulfide bonds in cyclic peptides are stable during 99mTc complexation reactions, and contradictory results have been reported regarding the integrity of disulfide bonds in cyclic somatostatin analogs. To estimate the stability of the disulfide bond in a synthetic somatostatin analog at low peptide concentrations, [125I]I-RC-160, in which radioiodine was incorporated into the 3-Tyr residue, was synthesized and the integrity of the disulfide bond of the peptide was investigated in the presence of reducing agents such as ascorbic acid, dithionite, and stannous ions. The disulfide bond in [125I]I-RC-160 remained stable in the presence of ascorbic acid in boiling water. The disulfide bond was also stable when treated with stannous ions at concentrations sufficient to reduce 99mTc for complexation with a thiol-free chelating agent, bis(hydroxamamide) analog when the 99mTc complexation reaction was performed at room temperature. However, the disulfide bond of [125I]I-RC-160 was slightly cleaved in the presence of a small amount of stannous ions when the reaction was performed in boiling water. Treatment of [125I]I-RC-160 with dithionite in boiling water markedly reduced the disulfide bond of the parental peptide. These findings indicated that synthetic somatostatin analogs may be labeled with 99mTc with stannous ions as the reducing agent without impairing their structure after conjugation of thiol-free chelating agents that provide 99mTc chelates under mild reaction conditions.
    Nuclear Medicine and Biology 12/1999; 26(8):883-90. · 2.52 Impact Factor
  • K Horiuchi, H Saji, A Yokoyama
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    ABSTRACT: Radiolabeling with rhenium (Re-186, Re-188), a tumor agent to resemble the pentavalent polynuclear technetium complex of dimercaptosuccinic acid (99mTc[V]-DMS) has been reported for radiotherapeutical use. Nevertheless, despite the periodic analogies between both radiometals, differences in the redox potential and the carrier concentration have made the radiolabeling of the rhenium counterpart difficult. In the present study, the effect of the carrier contained in the reactor-produced Re-186 was estimated as an important factor relevant to the Re-186 radiolabeling of DMS at an alkaline pH. Great effect of the carrier Re with an inverse correlation with the stannous ion was an interesting phenomenon relevant for an assumption on the Sn participation in the complex. Under strict control of various labeling parameters, the 186Re(V)-DMS was made available with high yield (93-97%) at an alkaline pH and at room temperature. The great effect of carrier offers support to the polymeric or polynuclear nature of the rhenium complex of DMS as depicted in the drug design basis of its parent Tc(V)-DMS. The biodistribution studies of Re(V)-DMS showed mimetic characteristics with its parent Tc(V)-DMS drug.
    Nuclear Medicine and Biology 11/1999; 26(7):771-9. · 2.52 Impact Factor
  • K Horiuchi, H Saji, A Yokoyama
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    ABSTRACT: Numerous clinical studies with the pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] seem to indicate its new role in nuclear oncology. Thus, we questioned what properties of the Tc(V)-DMS molecule associate with its tumoral tissue accumulation. Because studies have reported tumor tissue to be more acidic than normal tissue, acidification might be related to the Tc(V)-DMS localization in tumor tissue. Thus, in the present study, a working hypothesis drew to test the acidification as a plausible factor, and various analytical methods and an in vitro cellular system using Ehrlich ascites tumor cells (EATC) implemented. Analytical methodologies demonstrated the decrease of the overall negative charge of the Tc(V)-DMS molecule, promoted by the acidification of the analytical medium and the sample dilution. In the in vitro cellular experiment, acidification alone showed no effect on the radioactivity accumulation in EATC; nevertheless, if accompanied by a pre-dilution of the Tc(V)-DMS sample added into the cell incubation media, cellular radioactivity accumulation was observed. Thus, acidification as a mediator for the Tc(V)-DMS accumulation in tumoral cells, concurrently with dilution as the promoter of the process, constituted the foundation for discerning the working hypothesis.
    Nuclear Medicine and Biology 11/1998; 25(7):689-95. · 2.52 Impact Factor
  • K Horiuchi, H Saji, A Yokoyama
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    ABSTRACT: Since the conception of the pentavalent technetium polynuclear complex of dimercaptosuccinic acid, Tc(V)-DMS, a great number of papers published on its clinical applicability forced us to question "how tumor tissue appropriates the Tc(V)-DMS." Preliminary in vitro studies with Ehrlich ascites tumor cells (EATC) indicated the pH-sensitive character of this tumor agent. From this finding and the well-established notion that malignant tumors are more acidic than normal tissue, the in vivo correlation of Tc(V)-DMS accumulation in tumor tissue with its tissue acidification was considered of interest. The systemic lowering of tumor tissue pH by the stimulation of aerobic glycolysis has been well reported. In the present paper, the response of Tc(V)-DMS tumor accumulation to acidification induced by the glucose administration was explored in EATC-bearing mice. Measurement of tumor tissue pH was carried out by direct microelectrode technique and by histochemical umbelliferone technique in tumor tissue excised from EATC bearing mice. The regional acidity distribution is correlated with the regional radioactivity distribution registered by autoradiography. Evidence related to the pH sensitiveness of Tc(V)-DMS in response to glycolytic acidification was gathered; the pH measurement and the in vivo biodistribution of the double-tracer macroautoradiography with C-14 deoxyglucose (C-14-DG) demonstrated that the regional tissue distribution of Tc(V)-DMS was superimposed to that of C-14-DG. The glucose interventional modality offers the premier foundation for the interpretation of Tc(V)-DMS accumulation in diagnostic studies of malignant tumors.
    Nuclear Medicine and Biology 09/1998; 25(6):549-55. · 2.52 Impact Factor
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    ABSTRACT: The sensitivity of the IRMA method is limited by the specific activity (SA) of the conventionally employed radioisotropic label and high sensitivity radioimmunoassay should theoretically be attained by the use of short-lived radiometallic nuclides. Our group have achieved radiolabeling of high SA IgG by using the radiometal, gallium-67 (67Ga) with a short half-life (T1/2 = 78 h) and deferoxamine (DF), a bifunctional chelating agent bound through a multispacer (dialdehyde starch, DAS) as the linker (J Nucl Med 32:825, 1991). In the present work, the application of the approach is attempted by employing a two-site IRMA for human growth hormone (hGH); the monoclonal antibody to hGH (MAB2) is bound to DF via DAS and the coupled DF-DAS-MAB2 is radiolabeled with 67Ga. The 67Ga-DF-DAS-MAB2 of high SA (4,884 MBq/mg versus 370-518 MBq/mg calculated for radioiodinated MAB2) was thus used for the two site 'sandwich' 67Ga-IRMA. Excellent correlation with the 125I-IRMA was registered, and higher detection capability obtained by using 67Ga over the 125I in the hGH IRMA offered a good basis for the exploitation of short-lived radio-nuclides in the IRMA system.
    Annals of Nuclear Medicine 03/1996; 10(1):49-55. · 1.41 Impact Factor
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    ABSTRACT: To search for the tumour localization mechanism of Tc(V)-DMS, a polynuclear pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS], the development of medullary thyroid carcinoma (MTC) bearing mouse model was considered. Subcutaneously transplanted tumour was allowed to grow for 2, 4 and 6 weeks, and the influence of the tumour stage on the biodistribution of Tc(V)-DMS was screened. High radioactivity uptake in the tumour tissue was observed, and this accumulation showed a direct correlation with tumour growth and calcitonin secretion, the MTC marker detectable in the blood serum. The gathered data implicated some calcitonin-related factors as the mediator in the Tc(V)-DMS localization; participation of a phosphate-like oxoanion, TcO4 3–, is strongly suggested not only by the high radioactivity accumulation in the calcitonin-producing tumour but also by the accumulation in the bones of this model animal.
    European journal of nuclear medicine and molecular imaging 09/1991; 18(10):796-800. · 5.11 Impact Factor
  • K Horiuchi, I Yomoda, H Ohta, K Endo, A Yokoyama
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    ABSTRACT: To search for the tumour localization mechanism of Tc(V)-DMS, a polynuclear pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS], the development of medullary thyroid carcinoma (MTC) bearing mouse model was considered. Subcutaneously transplanted tumour was allowed to grow for 2, 4 and 6 weeks, and the influence of the tumour stage on the biodistribution of Tc(V)-DMS was screened. High radioactivity uptake in the tumour tissue was observed, and this accumulation showed a direct correlation with tumour growth and calcitonin secretion, the MTC marker detectable in the blood serum. The gathered data implicated some calcitonin-related factors as the mediator in the Tc(V)-DMS localization; participation of a phosphate-like oxoanion, TcO4(3-), is strongly suggested not only by the high radioactivity accumulation in the calcitonin-producing tumour but also by the accumulation in the bones of this model animal.
    European Journal of Nuclear Medicine 02/1991; 18(10):796-800.
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    ABSTRACT: Modification of the chelate ring structure of technetium-99m (99mTc) dithiosemicarbazone (DTS) chelate was carried out in pursuit of a more stable and lipophilic compound. A new DTS chelating molecule, pentane-2,4-dione bis(N-methylthiosemicarbazone) (PETS), with a 5-6-5 membered chelate ring structure, was synthesized and labeled with 99mTc, PETS generated two 99mTc compounds as major products. Both had much higher stability and lipophilicity than a 5-5-5 membered 99mTc DTS compound, as well as great stability in plasma. Both 99mTc-PETS compounds were rapidly extracted by the brain and heart when injected into mice. Thus, the modified chelate ring structure afforded a preferable characteristics to DTS chelate as for the chelating site for technetium radiopharmaceuticals.
    CHEMICAL & PHARMACEUTICAL BULLETIN 12/1990; 38(11):3099-101. · 1.56 Impact Factor
  • K Horiuchi, H Saji, Y Arano, A Yokoyama
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    ABSTRACT: In our pursuit for liver functional diagnosis, development of bifunctional radiopharmaceutical containing iminodiacetic acid (IDA), as the technetium chelating site along with phthalein or fluorescein structure, the skeleton of BSP and Rose Bengal, long used for the assessment of liver function is considered. Among the various PC, PPC, TPC and calcein IDA derivatives commercially available, 99mTc-PC (PC: 3,3'-bis(N, N-dicarboxymethylaminomethyl)o-cresolphthalein) showed the highest hepatobiliary excretion. The functionality of the various technetium labeled phthalein and fluorescein IDA derivatives was evaluated by competitive BSP binding studies and by comparative binding with the hepatocyte specific protein, ligandin.
    European Journal of Nuclear Medicine 02/1990; 16(3):137-42.
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    ABSTRACT: For the development of 62Cu labeled fatty acid analogs, two fatty acid analogs, containing dithiosemicarbazone (DTS) molecule as the 62Cu coordinating site, were designed and synthesized: a fatty acid analog containing DTS molecule at the omega-position, (a) the 12,13-dioxotetradecanoic acid di(N-methyl-thiosemicarbazone) (FA-DTS), and an omega-phenyl fatty acid analog containing DTS molecule at the para-position, (b) the p-carboxyundecylphenylglyoxal-di (N-methylthiosemicarbazone] (PFA-DTS). FA-DTS was synthesized by the reaction of ethyl diethoxyacetate with ethyl 11-bromonundecanate by successive decarboxylation and hydrolysis and final condensation with N-methylthiosemicarbazide. PFA-DTS was synthesized by the Friedel-Craft acylation of ethyl 11-phenylundecanate, selenium oxidation of the acetophenone derivative, followed by the condensation with N-methylthiosemicarbazide. Radiolabeling of FA-DTS and PFA-DTS with [64Cu]copper acetate was simple, rapid and quantitative. When injected into mice, both compounds were distributed and retained in the myocardium. These results offer a good basis for further development of 62Cu labeled fatty acid analogs.
    International Journal of Radiation Applications and Instrumentation Part A Applied Radiation and Isotopes 02/1989; 40(9):745-9.
  • Journal of computer assisted tomography 01/1989; 13:67-70. · 1.38 Impact Factor
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    ABSTRACT: Gadolinium-phthalein complexone (Gd-PC) was developed as a hepatobiliary magnetic resonance (MR) contrast agent. Phthalein complexone is one of the iminodiacetic acid derivatives and a structural analogue of bromosulfophthalein. Gadolinium-PC substantially enhanced signal intensity of normal functioning livers on T1-weighted MR images. Contrast enhancement of rabbit liver and gradual accumulation of high intensity bile in the gallbladder were observed after intravenous injection of 0.05 and 0.1 mmol/kg Gd-PC. However, 0.1 mmol/kg of Gd-DTPA caused little effect on liver MR.
    Journal of Computer Assisted Tomography 01/1989; 13(1):67-70. · 1.58 Impact Factor
  • Journal of Labelled Compounds 01/1989; 26(1‐12).
  • A. Yokoyama, I. Yomoda, K. Horiuchi
    Journal of Labelled Compounds 01/1989; 26(1‐12).
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    ABSTRACT: Considering the favourable nuclear properties of 99Tcm over 67Ga, we have developed a new tumour-seeking agent, 99Tc(V)m dimercaptosuccinic acid (Tc(V)-DMSA). In order to evaluate the clinical usefulness of Tc(V)-DMSA scintigraphies, 492 patients were studied with Tc(V)-DMSA, and in some cases, where possible, the results were compared with conventional 67Ga citrate scintigraphies. There was a high degree of usefulness of Tc(V)-DMSA in patients with head and neck tumours, medullary thyroid carcinomas and soft tissue tumours. But in patients with carcinomas of the lung, liver and gastrointestinal tract, malignant melanoma and lymphoma, Tc(V)-DMSA was of no or little use.
    Nuclear Medicine Communications 03/1988; 9(2):105-16. · 1.38 Impact Factor
  • 35th Annual Meeting of the Society of Nuclear Medicine, San Francisco, U.S.A.; 01/1988
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    ABSTRACT: In vivo dopamine receptor binding of the newly synthesized ligand, 125I-2'-iodospiperone (125I-2'-ISP), was studied in mouse brain. The highest accumulation was found in the striatum. Analysis of the striatal homogenate showed the 125I-2'-ISP to be metabolically stable. Furthermore, this striatal binding was saturable and displaced only by dopaminergic drugs. On the other hand, the accumulation in the cortex was as low as that of the cerebellum and uneffected by the administration of serotoninergic drugs and dopaminergic drugs; results assessed by macroautoradiographic studies. Thus, the newly synthesized 125I-2'-ISP presented high affinity for dopamine receptors in vivo and therefore, holds great potential for the in vivo dopamine receptor studies, provided 123I becomes readily available.
    Life Sciences 11/1987; 41(17):1999-2006. · 2.56 Impact Factor