Biomedical subjects
Publications and source records attributed to H Saji.
The linkage analysis between the locus for coagulation factor XIII-A (F13A) and HLA region genes (HLA-A, -C, -B) was performed. In males, the maximum of lod scores between F13A and HLA was 0.33 at 0 = 0.30, and in females lod scores were negative at all values of 0. The results provided no evidence for close linkage between F13A and HLA genes.
Recently, technetium-99m (99mTc) labeling of proteins through the use of a bifunctional chelating agent (BCA) has been reported. In previous work, a BCA containing a di(N-methylthiosemicarbazone) (DTS) moiety for 99mTc has offered good potential; however, conjugation with bulky proteins has induced some steric interference in the 99mTc labeling step using the stannous chloride method. In order to minimize this effect, changes in the hydrocarbon chain length (spacer) between the DTS and the protein binding site (carboxyl group), as well as the chemical state of the reducing agent, stannous chloride, were considered of interest. DTS molecules with variable spacer length (n = 0, 2, 4) were synthesized, coupled with human serum albumin and labeled with 99mTc. Also, stannous chloride prepared in different media was evaluated. Validity of the present approach is tested and discussed.
Development of 99mTc-bifunctional radiopharmaceutical (BR) is attracting the interest of various research groups. In the present paper, various molecules containing a neutral 99mTc-dithiosemicarbazone (DTS) structure as the technetium chelating site, along with various functional groups (amino, carboxyl or isobutyl group with diverse charge) are tested for their chemical or biological functions. The study on the effect of those functional groups is carried out in vitro and in vivo. The validity of introducing an amino group along with the technetium chelating site DTS for myocardial accumulation is discussed.
Several bifunctional radiopharmaceuticals (BR), molecules containing a neutral 99mTc-dithiosemicarbazone (DTS) structure as a chelating site, along with a functional amino group (primary tertiary and quaternary amino group) are tested for their chemical or biological functionalities as myocardial agents. Investigation of these amino compounds is carried out in vitro and in vivo. Mice (ddY) distribution studies show a high radioactivity distribution in heart with every tested derivative, but the highest heart to blood ratio of 2.92 (1 h) is achieved with the quaternary amino DTS. Also, this derivative displays low lung uptake inducing a proper target/non-target ratio for myocardial agent. The role conveyed by the various amino containing side chain in the biodistribution and validity of DTS derivative as BR are discussed.
A new bifunctional chelating agent, p-carboxyethylphenylglyoxal-di(N-methylthiosemicarbazone) (CE-DTS), containing a di(N-methylthiosemicarbazone) as the technetium coordinating site and an aralkyl carboxylate site for the protein conjugation was synthesized. Coupling to human serum albumin (HSA), selected as a model protein was carried out by the phosphorylazide method using diphenylphosphoryl azide (DPPA). The conjugation level of CE-DTS to HSA played a critical role in its biological evaluation. A 99mTc-CE-DTS-HSA with high in vivo stability was obtained when CE-DTS was coupled to HSA at 1:1 molar ratio. This compound showed similar in vivo stability to 131I labeled HSA in mice and rabbits.
As a basic structure of a bifunctional radiopharmaceutical (BR), dithiosemicarbazone (DTS) enables the formation of a small conjugated chelating ring with divalent metals (Cu2+, Zn2+, Ni2+), yielding stable and compact complexes. In the development of a neutral and compact monomeric DTS complex of technetium (99mTc), a DTS containing ligand, kethoxal-bis(thiosemicarbazone) (KTS) was selected. A well known monomeric Cu-KTS complex (or 64Cu-KTS) is taken as a model compound, and in vitro (TLC, EP, HPLC) and in vivo (mice biodistribution) studies were compared. Using the stannous chloride method, under conditions to avoid the hydrolytic polynucleation of technetium, a good yield of 99mTc-KTS with characteristics resembling the non-charged, compact and stable Cu-KTS is obtained, in in vitro as well as in vivo studies. The importance of DTS as the constituent of a BR is discussed.
As Zn is closely associated with the exocrine and endocrine functions of the pancreas, exploitation of Zn metabolism for anatomical and functional diagnosis was conceived, namely with the recent availability of positron emitting 62Zn (t1/2 = 9 h). In the present paper, response changes in Zn biodistribution (mice) and Zn excretion through the pancreatic duct (rats) due to the stimulation of gastro-intestinal hormones like secretin, CCK-PZ (exocrine stimulation) and glucose (endocrine stimulation) were studied. Under these stimuli, the pancreatic secretion of radioactive Zn through cannulated pancreatic duct showed increased Zn secretion only under the CCK-PZ effect, 3 h post 65Zn (t1/2 = 270 d) injection. Tissue biodistribution in mice pre-injected with 65Zn showed pancreas specific decrease of radioactive Zn whenever a gastro-intestinal hormone was post-administered, whereas the glucose effect was negligible. Thus, the effective mobilization of the injected radioactive Zn, upon exocrine stimulation, represented by CCK-PZ, favored the exploration of a functional study of the pancreas with the positron computed tomograph (PCT) using short lived nuclide labeled 62Zn-EDDA in dog. Evidence of the applicability of this system in regional function studies of the pancreas was obtained. Demonstration of Zn participation in the exocrine function of the pancreas in-vivo holds considerable promise for diagnosis of pancreatic diseases.
The metabolic pathway of radioactive 62Zn-EDDA (ethylenediamine-N,N'-diacetic acid), in the exocrine pancreas was studied with respect to that of endogenous Zn. In pancreatic duct cannulated dog, the secretion of intravenously injected exogenous 62Zn into pancreatic juice increased under the stimulation of CCK-PZ (pancreatic protein secretion stimulating hormone), which closely correlated to endogenous Zn. Moreover, in pancreatic juice, 62Zn as well as endogenous Zn was selectively bound to Zn-metalloenzymes, carboxypeptidase A and B. These results demonstrated the close correlation between the endogenous and the exogenously-administered Zn (62Zn-EDDA), as well as the high availability of 62Zn-EDDA as a marker of pancreatic function for the follow up of carboxypeptidase metabolism.
The effect of low sensitivity areas or gaps between adjacent slices of the multislice positron emission tomography on detection of myocardial perfusion abnormality with 13NH3 was evaluated segmentally in 36 patients with coronary artery disease at rest or during exercise. The detectability of the defects in RCA or LAD region was 80% in single-position scans in stress studies. The false-negative defects were located mainly in the inferior wall, apicoinferior wall, or high anterior wall. When the patients were moved half the slice interval to perform the interpolating scan, and the two sets of images were interlaced with each other, the detectability increased to 88%. The interpolating scan also allowed reconstruction of long-axis and short-axis tomograms in high quality, which further improved the detectability of perfusion defects (100% for RCA or LAD and 75% for LCX lesion) and helped in understanding the anatomic relationships to the coronary artery territories.
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In our search for a platelet-specific labeling agent, metaraminol (MA), a low-toxic pharmaceutical for the treatment of hypotension and cardiogenic shock, attracted our attention. Its active incorporation and accumulation by platelets have been recognized. At first, the preparation of 125I radioiodinated metaraminol (125I-MA) was carried out using the chloramine-T method. Then, upon the harvest of platelets as platelet-rich plasma (PRP), their labeling with this new radiopharmaceutical was easily performed by incubation for 10 min at 37 degrees C. The cell-labeling efficiency was dependent on cell density, reaching 63.0% +/- 3.1% at 2.4 X 10(9) cells/ml. The specific incorporation of 125I-MA by an active transport system similar to that of 5-hydroxytryptamine (5-HT) as well as by passive diffusion was demonstrated. In in vitro studies, the unaltered state of 125I-MA-labeled platelets with their cellular functions fully retained was estimated. In vivo studies carried out in rabbits with induced thrombi in the femoral artery showed a rather rapid disappearance of the radioactivity from circulating blood, reaching a high thrombus-to-blood activity ratio of 19.8 +/- 4.3 within 30 min of the administration of 125I-MA-labeled autologous platelets. Thus, with the potential availability of 123I, 123I-MA-labeled platelets appear to be a promising agent for thrombus imaging using single-emission computed tomography (CT) studies.
To assess the value of myocardial-perfusion positron computed tomography (PCT) for the evaluation of coronary artery disease (CAD), 13N-ammonia PCT using a whole-body multislice PCT device was performed at rest and during exercise in 6 normal subjects and 19 patients with angiographically documented CAD. The 13N-ammonia distribution in the myocardium was assessed both qualitatively and quantitatively. At rest and during exercise, the tracer distribution was homogeneous in the 6 normal cases. In the 19 patients with CAD, regional hypoperfusion was observed in 14 cases (74%) at rest and in 18 cases (95%) during exercise. Additional perfusion abnormalities were detecting during exercise in 12 cases. Segmental analysis of the myocardial perfusion identified 30 out of 34 stenosed vessels (88%) during exercise, with only one false-positive finding of diseased vessels (specificity, 98%). For the quantitative analysis of myocardial perfusion by PCT, the percentage of change in the tracer concentration in the same region between the rest and stress images was calculated. The concentration was slightly increased in normal myocardial segments (14.4% +/- 5.8%; P less than 0.001), whereas in CAD, it was significantly decreased in segments with stenosed vessels (-18.0% +/- 18.3%; P less than 0.02). We conclude that 13N-ammonia PCT at rest and during exercise provides high-quality images, and is a sensitive and effective technique for detecting CAD and identifying individual stenosed vessels. Furthermore, this technique makes possible quantitative assessment of the coronary reserve function.
Highly purified high and low molecular weight urokinase (H-UK and L-UK) were labeled with 67Ga using deferoxamine (DF) as a bifunctional chelating agent. The labeling efficiency was 91.7% for the H-UK, and 90.4% for the L-UK, respectively. The 67Ga labeled UK (67Ga-DF-UK) fully retained the enzymatic activity of the parent UK. Studies on the in vivo behavior of the 67Ga labeled UK in rabbits showed a very rapid blood clearance with half-life of 4 min (67Ga-DF-L-UK) to 8 min (67Ga-DF-H-UK). Studies carried out in rabbits with induced thrombi in the femoral vein showed thrombus-to-blood 67Ga-DF-UK activity ratios, 2h after injection, of 2.00-3.08 for the H-UK, and 0.84-1.65 for the L-UK, respectively, with thrombi aged 4 to 3 days. A dose effect of the 67Ga-DF-H-UK on its thrombus accumulation was observed. Gel chromatographic analysis of plasma samples withdrawn from those animals injected with this radiopharmaceutical revealed a reduction of the 67Ga-DF-UK effectiveness due to complexation with protein inhibitors. This led to formation of high molecular weight complexes which was reflected in the very fast blood clearance. Its implication in thrombus accumulation is discussed. In conclusion, usefulness of DF for labeling UK with 67Ga or 68Ga with no alteration of UK enzymatic properties was demonstrated. The use of 67Ga-DF-UK as a diagnostic or therapeutic radiopharmaceutical is promising.
In our search for a technetium-tumor seeking agent, the chemical characteristic of polynuclear Ga-citrate attracted our attention. On this basis, we selected the ligand dimercaptosuccinic acid (DMS) and appropriate labeling conditions in the design of 99mTc(V)-DMS. Chemical characterization was performed by thin layer chromatography, electrophoresis, Sephadex column chromatography and spectrophotometric studies at the chemical concentration (99Tc). Biodistribution in mice bearing Ehrlich ascites tumor and scintigraphic images in VX-2 tumor-bearing rabbit, indicated the great applicability of 99mTc(V)-DMS as a new tumor imaging agent. Its distinctive characteristic, different from the kidney imaging agent (99mTc-DMSA) is demonstrated and the biological implication of hydrolytic polynucleation of pentavalent technetium, through an anionic specie Tc(V)O3-(4), in the tumor cell is discussed.
Increasing interest in the short-lived radionuclide 68Ga (t1/2: 68.2 min) has revived basic studies of gallium radiopharmaceuticals. Ga-citrate (Ga-cit), described as a polynuclear complex, possesses great affinity for tumor cells but is also bound by blood transferrin (Tf). Exploitation of reaction-rate differences in metal ion transference from Ga-cit to Tf (slow) and Fe-nitrilotriacetate (Fe-NTA) to Tf (fast) is put to use to attain a proper tumor/tissue ratio within practical time limits. Studies on administration mode, time and dose offered promising results for future 68Ga-cit tomographic studies.