Biomedical subjects

Y Fujibayashi

Publications and source records attributed to Y Fujibayashi.

At least 19 recordsLinked to original sources

PubMed1996

Applicability of short-lived radiometallic nuclide for high sensitivity two-site "sandwich" immunoradiometric assay: human growth hormone assay.

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.

Antibodies, Monoclonal↗

PubMed1996

Evaluation of myocardial viability with iodine-123-BMIPP in a canine model.

UNLABELLED: The tracer 123I-BMIPP was examined for its ability to reflect myocardial lipid metabolism. Studies in mice indicate that myocardial BMIPP uptake correlates with ATP content. Details, however, of myocardial accumulation in the ischemic period with either infarct or ischemia are not well documented. METHODS: Sixteen adult mongrel dogs were investigated. The occluded left anterior descending artery (LAD) alone was reperfused to make the ischemic area, and the first diagonal branch of the LAD was kept occluded to make the infarct area. Regional wall motion was evaluated by echocardiography in the short-axial view from the epicardium. Tissue blood flow was calculated using nonradioactive colored microspheres. Changes in blood glucose levels, lipid levels and lactate extraction were examined in blood collected from the aorta and great cardiac vein (GCV). The ATP concentration and BMIPP count were determined by high-performance liquid chromatography and gamma-counter, respectively. RESULTS: Two hours after reperfusion, blood flow decreased to 20% +/- 5% in the infarct area and 64% +/- 9% in the ischemic area (p < 0.05), despite comparable wall-motion reduction (32% +/- 5% and 42% +/- 12% in the infarct and ischemic areas, respectively). BMIPP content and ATP concentration showed parallel reduction: 40% +/- 7% and 75% +/- 4% (p < 0.05) of BMIPP and 32% +/- 9% and 69% +/- 7% (p < 0.05) of ATP in the infarct and ischemic areas, respectively. The nonesterified fatty acid extraction, defined as flow x ([artery] - [GCV]), decreased to 87% +/- 5.6% during occlusion and 75% +/- 20.1% 2 hr after reperfusion, as compared with the control value. CONCLUSION: BMIPP uptake correlated well with lipid metabolism and tissue ATP levels and may prove useful in differentiating myocardial infarction from ischemia in the acute phase of ischemic episodes.

Adenosine Triphosphate↗

PubMed1996

[Basic studies on the 111In labeled antisense oligonucleotide for tumor imaging].

Antisense oligonucleotide labeled with short lived radionuclide has been proposed as a radiopharmaceutical for the detection of abnormal gene expression. In this study, plausibility of 32P or 111In labeled oligonucleotide was basically evaluated using c-erbB-2 protooncogene mRNA as a model target. In cell uptake studies, sequence specific accumulation of 32P-oligonucleotide was found in the cells with c-erbB-2 mRNA expression, but not control cells, indicating the basic possibility of antisense strategy. Synthesis of 111In labeled isothiocyanobenzyl-EDTA (IBE)-oligonucleotide could be performed, but some problems were found in purification step. Stability of 111In-IBE-oligonucleotide was high when compared with that of 32P-oligonucleotide, and in vivo biodistribution data might indicate that 111In-IBE-oligonucleotide was plausible for tumor imaging.

Animals↗

PubMed1996

Metabolic fate of iodine-123-BMIPP in canine myocardium after administration of etomoxir.

UNLABELLED: To clarify the metabolic fate of 123I-(-p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in dysfunctional myocardium, a comparison between normal dogs and those with etomoxir administration was studied using an open-chest canine model. METHODS: Using open-chested dogs under anesthesia, we created a system to release all the blood in the great cardiac vein outside without recirculation, if necessary. Iodine-123-BMIPP was directly injected into the left anterior descending artery, its extraction, retention and washout rate in the early phase were calculated, and the metabolites in the myocardium were evaluated using a high-performance liquid chromatography. Moreover, these factors were compared between normal dogs and those pretreated with etomoxir, that creates a condition similar to ischemia. RESULTS: Although rapid extraction of BMIPP from the plasma into the myocardium and the subsequent retention were unchanged, early washout (8 min) of radioactivity significantly increased (49.6% +/- 13.3%-->70.5% +/- 10.7%, p < 0.05) with etomoxir. The levels of the full metabolite formed by complete oxidation of BMIPP decreased significantly with etomoxir (21.4% +/- 10.9%-->5.5% +/- 3.5%, p < 0.01). In addition, back diffusion of BMIPP increased (25.1% +/- 8.0%-->41.9% +/- 12.0%, p < 0.05) in the etomoxir-treated animals without affecting the levels of alpha-oxidation metabolite and the intermediate metabolites. CONCLUSION: BMIPP is very sensitive to etomoxir and is suitable for assessing mitochondrial dysfunction. Iodine-123-BMIPP might be a promising radiopharmaceutical for the evaluation of ischemic heart disease, cardiomyopathy and mitochondrial encephalomyopathy.

Animals↗

PubMed1996

Generator-produced copper-62-PTSM as a myocardial PET perfusion tracer compared with nitrogen-13-ammonia.

UNLABELLED: The purpose of this study was to determine the suitability of 62Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) (62Cu-PTSM) for estimating myocardial blood flow (MBF) over a wide range of flow by comparison with 13N-ammonia (13NH3). METHODS: PET studies using 62Cu-PTSM and 13NH3 were performed at rest and after pharmacological vasodilatation in 9 normal subjects and 13 patients with coronary artery disease (CAD). According to the microsphere method, values for the product of the extraction fraction and MBF (ExMBF) were calculated using both tracers. In static images, the percent uptake (normalized to the peak count) of each tracer was measured in patients with CAD. RESULTS: The myocardial tracer distribution in the normal subjects was significantly higher in the inferior wall in the 62Cu-PTSM studies and lower in the lateral wall in the 13NH3 studies. The ExMBF values showed linear correlation for both tracers in a low flow range. In a high flow range, however, the ExMBF values for 62Cu-PTSM were nonlinearly proportional to the increase of those for 13NH3 (y = 1.1 x -0.21x2, r = 0.81). The percent uptake for both tracers at baseline well correlated linearly (y = 10.4 + 0.88x, R = 0.91). After pharmacological vasodilatation underestimation of blood flow with 62Cu-PTSM was noted compared to that with 13NH3 at high flows (y = 31.8 + 0.63x, r = 0.76). CONCLUSION: These results suggest that the MBF estimates using 62Cu-PTSM in a low flow range may be as accurate as those with 13NH3. In a high flow range, however, the extraction fraction of 62Cu-PTSM is considered to be lower than that of 13NH3, and this may limit the estimation of MBF with 62Cu-PTSM after pharmacological vasodilatation.

Ammonia↗

PubMed1996

Metabolism and kinetics of iodine-123-BMIPP in canine myocardium.

UNLABELLED: The kinetics and metabolic fate of 123I-15-(p-iodophenyl)-3-(R,S)- methylpentadecanoic acid (BMIPP) in canine myocardium were studied in an open-chest dog model. METHODS: After left anterior descending artery injection of BMIPP, blood samples were collected from the corresponding great coronary vein (V) and femoral artery (A). On the basis of the A-V radioactivity difference as well as the HPLC elution profile at various time points, myocardial extraction, retention and metabolism of BMIPP were evaluated. RESULTS: BMIPP was instantly extracted from the plasma into the myocardium (74% of the injected dose) and was then retained (65.3%). Washout of the retained radioactivity was low (8.7%) and most of the washout was as alpha- and beta-oxidation metabolites (2.3 + 2.9 + 1.4%), with little loss of BMIPP itself (2.1 %). CONCLUSION: BMIPP is suitable for static SPECT imaging of the myocardium, and its slow washout appears to be due to metabolism through alpha- and beta-oxidation.

Animals↗

PubMed1996

Measurement of regional cerebral plasma pool and hematocrit with copper-62-labeled HSA-DTS.

UNLABELLED: We developed copper-62-labeled human serum albumin-dithiosemicarbazone (62Cu-HSA-DTS) as a blood-pool imaging agent for PET. To evaluate 62Cu-HSA-DTS for plasma-pool imaging and to measure the regional cerebral hematocrit, 12 normal volunteers and 7 patients with cerebrovascular disease underwent PET studies with 62Cu-HSA-DTS and 15O-labeled carbon monoxide (C15O). METHODS: The normal subjects were studied with both C15O and 62Cu-HSA-DTS. All patients were examined by 15O-gas studies to measure cerebral perfusion and oxygen metabolism, followed by measurement of plasma volume with 62Cu-HSA-DTS for analysis of regional cerebral hematocrit. Regional cerebral hematocrit was calculated from regional cerebral red cell volume (rCRCV) measured by C15O and regional plasma volume (rCPV) measured by 62Cu-HSA-DTS in each subject, and the regional cerebral/large-vessel hematocrit ratio was obtained for both cerebral hemispheres in each subject. RESULTS: Mean regional cerebral hematocrit and mean cerebral/large-vessel hematocrit ratio in the 12 normal volunteers were 38.3 +/- 3.45% and 0.88 +/- 0.06, respectively. In the seven patients with cerebrovascular disease, regional cerebral hematocrit was significantly lower on the hypoperfused side than the normal hemisphere. The images of rCPV and rCRCV from these patients demonstrated a greater increase in rCPV than rCRCV in the hypoperfused area. CONCLUSION: These results suggest that 62Cu-HSA-DTS can be used for measurement of plasma volume and that regional cerebral hematocrit may provide valuable information regarding the microcirculation in the brain.

Adult↗

PubMed1996

Measurement of regional cerebral blood flow with copper-62-PTSM and a three-compartment model.

UNLABELLED: We evaluated quantitatively 62Cu-labeled pyruvaldehyde bis(N4-methylthiosemicarbazone) copper II (62Cu-PTSM) as a brain perfusion tracer for positron emission tomography (PET). For quantitative measurement, the octanol extraction method is needed to correct for arterial radioactivity in estimating the lipophilic input function, but the procedure is not practical for clinical studies. To measure regional cerebral blood flow (rCBF) by 62Cu-PTSM with simple arterial blood sampling, a standard curve of the octanol extraction ratio and a three-compartment model were applied. METHODS: We performed both 15O-labeled water PET and 62 Cu-PTSM PET with dynamic data acquisition and arterial sampling in six subjects. Data obtained in 10 subjects studied previously were used for the standard octanol extraction curve. Arterial activity was measured and corrected to obtain the true input function using the standard curve. RESULTS: Graphical analysis (Gjedde-Patlak plot) with the data for each subject fitted by a straight regression line suggested that 62Cu-PTSM can be analyzed by the three-compartment model with negligible K4. Using this model, K1-K3 were estimated from curve fitting of the cerebral time-activity curve and the corrected input function. The fractional uptake of 62Cu-PTSM was corrected to rCBF with the individual extraction at steady state calculated from K1-K3. The influx rates (Ki) obtained from three-compartment model and graphical analyses were compared for the validation of the model. A comparison of rCBF values obtained from 62Cu-PTSM and 150-water studies demonstrated excellent correlation. CONCLUSION: The results suggest the potential feasibility of quantitation of cerebral perfusion with 62Cu-PTSM accompanied by dynamic PET and simple arterial sampling.

Brain↗

PubMed1995

Clinical application of 62Zn/62Cu positron generator: perfusion and plasma pool images in normal subjects.

We have developed a new 62Zn/62Cu positron generator, and applied it for PET imaging of perfusion and plasma volume in 5 normal subjects. The generator makes it possible by a simple procedure to obtain 62Cu eluate and labeling compounds sufficiently every 40-60 minutes. 62Cu labeled pyruvaldehyde bis(N4-methylthiosemicarbazone) copper II (62Cu-PTSM) was employed for cerebral and myocardial perfusion imaging and 62Cu labeled human serum albumin-dithiosemicarbazone (62Cu-HSA-DTS) was used for plasma pool imaging. The images of cerebral blood flow, cerebral plasma volume and myocardial perfusion were excellent. In addition, the analysis of tissue activity and blood activity demonstrated the microspheric character of 62Cu-PTSM. Correction of arterial activity with the standard disappearance curve of 62Cu-PTSM suggested the possibility of quantifying blood flow. The results of this study indicate the capability of the 62Zn/62Cu generator for wide clinical use without an in-house cyclotron.

Adult↗

PubMed1995

Differential mechanism of retention of Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) by brain and tumor: a novel radiopharmaceutical for positron emission tomography imaging.

The reductive retention of 62Cu-PTSM was comparatively studied in the brain and Ehrlich ascites tumor cells by electron spin resonance spectrometry and nonradioactive Cu-PTSM. In the brain, only the mitochondrial fraction showed the ability to reduce Cu-PTSM, and the other subcellular fractions did not. In contrast, the cytosolic fraction of Ehrlich ascites tumor cells was the specific site of Cu-PTSM reduction. It was therefore considered that the retention of Cu-PTSM in the brain is closely related to mitochondrial reduction, most probably involving the mitochondrial electron transport system.

Animals↗

PubMed1995

Canine SPECT studies for cerebral amino acid transport by means of 123I-3-iodo-alpha-methyl-L-tyrosine and preliminary kinetic analysis.

We have already reported that 123I-3-iodo-alpha-methyl-L-tyrosine (123I-L-AMT) is superior as a single-photon emitter labeled radiopharmaceutical reflecting cerebral amino acid transport. In this study, we investigated the distribution of 123I-L-AMT in the canine head by means of SPECT and kinetically analyzed the data in the brain. As a result, clear SPECT images of the canine brain were obtained. Kinetic analysis with a 2-compartment model, including or expressing membrane transport of the amino acid, was performed with time-activity curves in the arterial blood and in the cerebral region. The results of the analysis coincided closely with the experimental data and the relevance of the model was strongly suggested. Therefore 123I-L-AMT is considered to be useful as a single photon radiopharmaceutical which enables us to measure the cerebral amino acid transport rate.

Amphetamines↗

PubMed1995

Amino acid transport after transient global ischemia in rats: quantitative autoradiographic study using 3-[125I]iodo-alpha-methyl-L-tyrosine.

We studied the influence of reperfusion on amino acid transport of the brain after transient global ischemia in rats. The animals were subjected to 30-min four-vessel occlusion according to the procedures developed by Pulsinelli prior to recirculation for 3, 6, 24, 48 and 72 h. We used 3-[125I]iodo-alpha-methyl-L-tyrosine as an autoradiographic tracer for selective cerebral amino acid transport maker. Following 30-min global ischemia, uptakes of 3-[125I]iodo-alpha-methyl-L-tyrosine were significantly (P < 0.05) lower in substantia nigra, striatum and ventral tegmental area (6, 24, 48 and 72 h post-reperfusion), but significantly (P < 0.05) higher in cortex and thalamus (3 and 6 h post-reperfusion). The influence of transient global ischemia on cerebral amino acid transport manifested region-specific three different patterns; namely, suppression, acceleration and no change in amino acid transport. The influence of transient ischemia on catecholamine-synthesizing brain sites is most remarkable.

Amino Acids↗

PubMed1995

Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM), a metal complex with selective NADH-dependent reduction by complex I in brain mitochondria: a potential radiopharmaceutical for mitochondria-functional imaging with positron emission tomography (PET).

The reductive retention mechanism of copper(II)-pyruvaldehyde-bis (N4-methylthiosemicarbazone) (Cu-PTSM), a generator-produced positron-emitting 62Cu-labeled radiopharmaceutical, was studied with non-radioactive and radioactive copper. Changes in the chemical form of Cu-PTSM were detected by electron spin resonance spectrometry (ESR) with cold copper. The effects of electron transport chain inhibitors on the reduction of Cu-PTSM were also examined. Rotenone and antimycin A activated the reduction of Cu-PTSM in the brain mitochondria by 1.6- and 1.4-fold, respectively, compared with untreated controls, while thenoyltrifluoroacetone (TTFA) had no effect on the reduction. These results were confirmed with radioactive copper. Furthermore, this reduction of Cu-PTSM was dependent on the protein concentration of mouse brain submitochondrial particle (SMP) with 1 mM NADH (0 mg-protein/ml: 1.8 +/- 2.5%, 8 mg-protein/ml: 69.0 +/- 5.5%, each value was % of reduced Cu). Similarly, this reduction depended on NADH concentration at a fixed concentration of SMP (8 mg-protein/ml). These results indicated that the electron transport chain, especially complex I, participated in the reduction of Cu-PTSM in brain mitochondria, and this suggested that Cu-PTSM has the potential to act as a functional imaging agent for diagnosis of the electron transport chain.

Animals↗

PubMed1995

Decreased uptake of iodinated branched fatty acid analog indicates metabolic alterations in ischemic myocardium.

UNLABELLED: We previously reported that uptake of 123I-labeled 15-iodophenyl 3-methyl pentadecanoic acid (BMIPP) was lower than that of thallium in ischemic myocardium. Such discordant findings between BMIPP and thallium were compared with those of PET using 18F-deoxyglucose (FDG) and 11C-acetate to assess metabolic alterations in such segment. METHODS: Sixteen patients with coronary artery disease underwent both BMIPP SPECT and PET. Relative FDG uptake (% FDG uptake) and the clearance rate constant (% Kmono) of 11C-acetate from the myocardium were calculated as markers of glucose and oxidative metabolism, respectively. RESULTS: Relative FDG uptake of the myocardial segments with reduced BMIPP uptake and normal thallium uptake (discordant segments) was similar (85.3 +/- 10.3) to that of the normal segments (86.5 +/- 11.7) but higher than that of segments with reduced uptake of both BMIPP and thallium (67.5 +/- 19.9). Similarly, the discordant segments showed a higher % Kmono value (77.8 +/- 13.1 versus 70.0 +/- 19.1) and FDG-to-perfusion ratio (1.15 +/- 0.08 versus 1.01 +/- 0.22) than in the concordantly reduced segments. CONCLUSION: BMIPP uptake appears to provide metabolic information independent of thallium uptake. Combined imaging of BMIPP and thallium may potentially identify ischemic but viable myocardium.

Acetates↗

PubMed1994

Copper(II)[2,3-butanedionebis(N4-methylthiosemicarbazone)], a stable superoxide dismutase-like copper complex with high membrane penetrability.

To obtain a superoxide dismutase (SOD)-like drug that could readily cross the cell membrane, we investigated the SOD-like activity, intracellular uptake, and stability of several Cu(II)Bisthiosemicarbazones (Cu(II)BTS). Among these Cu(II)BTS chelates, Cu(II)[2,3-Butanedionebis(N4-methylthiosemicarbazone)] (Cu(II)BMTS) was the most effective SOD-like compound with activity similar to activity reported for various previously reported SOD-like Cu complexes. Biodistribution studies in mice indicated that Cu(II)BMTS rapidly distributed to all tissues and readily crossed cell membranes as well as the blood-brain barrier with high distributions to the brain and the heart. Moreover, Cu(II)BMTS was stable in mouse brain homogenate and mouse blood. These results suggest that Cu(II)BMTS has the potential to be used as a SOD-like drug capable of reaching intracellular superoxide generating sites.

Animals↗

PubMed1994

Combined study with I-123 fatty acid and thallium-201 to assess ischemic myocardium: comparison with thallium redistribution and glucose metabolism.

To assess the clinical value of combined SPECT imaging with I-123-15-(p-iodophenyl)-3-methyl pentadecanoic acid (BMIPP) and thallium-201 (Tl), the findings were compared with those obtained in a stress Tl study and positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) in 22 patients with myocardial infarction. In 20 patients who underwent a stress Tl study, among 75 hypoperfused segments, 27 segments exhibited less BMIPP uptake than Tl (discordant segments), and the remaining 48 segments showed a similar decrease in BMIPP uptake (concordant segments). Twenty-two of 27 discordant segments (81%) exhibited redistribution on stress Tl study. On the other hand, only one of the 48 concordant segments had redistribution (p < 0.001). In 10 patients who underwent a FDG PET study, among 33 hypoperfused segments, seven segments were discordant segments, and the remaining 25 segments were concordant segments. Seven of the eight discordant segments (88%) demonstrated an increase in FDG uptake. In contrast, only five of 25 concordant segments (20%) showed increase in FDG uptake (p < 0.01). Thus, the segments showing discordant BMIPP uptake are considered to be ischemic but viable myocardium. We conclude that combined imaging with BMIPP and Tl is a useful mean for evaluating tissue viability in patients with coronary artery disease, but it may underestimate the extent of tissue viability, compared with FDG PET imaging.

Adult↗

PubMed1994

Differential aging pattern of cerebral accumulation of radiolabeled glucose and amino acid in the senescence accelerated mouse (SAM), a new model for the study of memory impairment.

Using an accelerated senescence-prone model mouse strain, SAMP8, with spontaneously occurring age-related deficits in learning and memory, cerebral glucose and amino acid accumulation were investigated to study the metabolic abnormalities in relation to age. The findings were compared with those in an accelerated senescence-resistant mouse strain, SAMR1, without deterioration of ability in learning and memory. [14C]-2-Deoxyglucose accumulation in the SAMP8 brain was normal at 1 month of age but decreased from 2-3 months of age onwards. In contrast, tyrosine accumulation was unchanged from 1 to 5 months of age. The impairment of memory in the SAMP8 at 2-3 months of age corresponded with the decrease in [14C]-2-deoxyglucose accumulation, but was not related to Tyr. This animal model may help provide new information on the metabolic changes in aging.

Aging↗

PubMed1994

Cu-ATSM, an intracellular-accessible superoxide dismutase (SOD)-like copper complex: evaluation in an ischemia-reperfusion injury model.

We have reported a stable superoxide dismutase (SOD)-like copper complex, Cu-ATSM, which shows high membrane permeability and distribution to the brain or heart. In this study, we evaluated the protective effects of Cu-ATSM on superoxide-mediated tissue damage caused by ischemia-reperfusion using an isolated perfused rat heart model. Lipid peroxidation levels in the Cu-ATSM treated group were lower than those in the non-treated group. Furthermore, released creatine phosphokinase into the perfusate, a marker of tissue damage, was reduced by Cu-ATSM treatment. These results indicated the possibility of Cu-ATSM being an effective SOD-like drug for the treatment of superoxide-mediated damage, such as ischemia-reperfusion injury.

Animals↗