Biomedical subjects

Hideo Saji

Publications and source records attributed to Hideo Saji.

At least 19 recordsLinked to original sources

PubMed2007

99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits.

PURPOSE: Apoptosis is commonly observed in advanced atherosclerotic lesions. 99mTc-annexin A5 (99mTc-annexin V) has been proposed as a potential tracer for imaging apoptosis in atherosclerotic plaques. Accordingly, we determined the usefulness of 99mTc-annexin A5 as an atherosclerosis imaging tracer in a rabbit model (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits; WHHLMI rabbits) of spontaneous atherosclerosis. METHODS: The WHHLMI and control rabbits were injected intravenously with 99mTc-annexin A5. After in vivo planar imaging, the radioactivity in the aorta was measured. Autoradiography, TUNEL staining, Azan-Mallory staining and immunohistological studies were performed serially throughout the aorta. RESULTS: 99mTc-Annexin A5 accumulation in the aorta of the WHHLMI rabbits was 5.6-fold higher than in that of control rabbits. Autoradiography showed heterogeneous multifocal accumulation of 99mTc-annexin A5 in WHHLMI rabbits. 99mTc-Annexin A5 accumulation was highest in the atheromatous lesions (6.2+/-2.5, %IDxBW/mm2x10(3)), followed in decreasing order by neointimal (4.9+/-1.3), fibroatheromatous (4.5+/-1.9), and collagen-rich lesions (3.3+/-1.4). The regional 99mTc-annexin A5 accumulation was significantly correlated with the TUNEL-positive cell density, macrophage density and "vulnerability index," an index of the morphological destabilized characteristics. The in vivo imaging clearly visualized the atherosclerotic lesions in WHHLMI rabbits. CONCLUSION: The present study in WHHLMI rabbits showed higher 99mTc-annexin A5 accumulation in grade IV atheroma than in other more stable lesions. 99mTc-Annexin A5 may be useful in identifying atheroma that is at higher risk for rupture and possibly in assessing the response to anti-atherosclerotic therapy.

Animals↗

PubMed2007

Therapeutic effects of a 186Re-complex-conjugated bisphosphonate for the palliation of metastatic bone pain in an animal model.

UNLABELLED: Previously, based on the concept of bifunctional radiopharmaceuticals, we developed a highly stable (186)Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate] oxorhenium(V) ((186)Re-MAG3-HBP), for the treatment of painful bone metastases. This agent showed a superior biodistribution as a bone-seeking agent in normal mice when compared with (186)Re-1-hydroxyethylidene-1,1-diphosphonate ((186)Re-HEDP). In this study, we evaluated the therapeutic effects of (186)Re-MAG3-HBP using an animal model of bone metastasis. METHODS: The model was prepared by injecting syngeneic MRMT-1 mammary tumor cells into the left tibia of female Sprague-Dawley rats. (186)Re-MAG3-HBP (55.5, 111, or 222 MBq/kg) or (186)Re-HEDP (55.5 MBq/kg) was then administered intravenously 21 d later. To evaluate the therapeutic effects and side effects, tumor size and peripheral blood cell counts were determined. Palliation of bone pain was evaluated by a von Frey filament test. RESULTS: In the rats treated with (186)Re-HEDP, tumor growth was comparable with that in untreated rats. In contrast, when (186)Re-MAG3-HBP was administered, tumor growth was significantly inhibited. Allodynia induced by bone metastasis was attenuated by treatment with (186)Re-MAG3-HBP or (186)Re-HEDP, but (186)Re-MAG3-HBP tended to be more effective. CONCLUSION: These results indicate that (186)Re-MAG3-HBP could be useful as a therapeutic agent for the palliation of metastatic bone pain.

Animals↗

PubMed2006

Is MIBG a substrate of P-glycoprotein?

PURPOSE: Radionuclide therapy with 131I-labelled meta-iodobenzylguanidine ([131I]MIBG) is effective in cases where it is difficult to carry out surgical resection or debulking of neuroendocrine tumours (NETs). However, it has recently been reported that P-glycoprotein (P-gp) is expressed in these NETs. Therefore, it is important to clarify whether MIBG is a substrate of P-gp or not. In this study, using a human cell line which overexpresses P-gp, LLC-GA5-COL150, we investigated this question. METHODS: The transcellular transport and accumulation of [125I]MIBG were measured using monolayer cultures grown in Transwell chambers. [125I]MIBG was added to either the basolateral or the apical side, aliquots of the incubation medium on the other side were taken at specified times, and the radioactivity was measured. For accumulation experiments, the cells on the filters were solubilised and the radioactivity in aliquots was measured. RESULTS: There were no significant differences in the transport of MIBG between LLC-PK1 and LLC-GA5-COL150 monolayers in either direction until 60 min. With respect to the accumulation of MIBG, there were no significant differences between LLC-PK1 and LLC-GA5-COL150 cells in either direction. CONCLUSION: MIBG is not a substrate of P-gp. Therefore, radionuclide therapy with MIBG would be useful in the treatment of NETs expressing P-gp.

3-Iodobenzylguanidine↗

PubMed2006

Novel benzofuran derivatives for PET imaging of beta-amyloid plaques in Alzheimer's disease brains.

A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.

Alzheimer Disease↗

PubMed2006

Development of a 111In-labeled peptide derivative targeting a chemokine receptor, CXCR4, for imaging tumors.

The chemokine receptor CXCR4 is highly expressed in tumor cells and plays an important role in tumor metastasis. The aim of this study was to develop a radiopharmaceutical for the imaging of CXCR4-expressing tumors in vivo. Based on structure-activity relationships, we designed a 14-residue peptidic CXCR4 inhibitor, Ac-TZ14011, as a precursor for radiolabeled peptides. For 111In-labeling, diethylenetriaminepentaacetic acid (DTPA) was attached to the side chain of d-Lys(8) which is distant from the residues indispensable for the antagonistic activity. In-DTPA-Ac-TZ14011 inhibited the binding of a natural ligand, stromal cell-derived factor-1alpha, to CXCR4 in a concentration-dependent manner with an IC50 of 7.9 nM (Ac-TZ14011: 1.2 nM). In biodistribution experiments, more 111In-DTPA-Ac-TZ14011 accumulated in the CXCR4-expressing tumor than in blood or muscle. Furthermore, the tumor-to-blood and tumor-to-muscle ratios were significantly reduced by coinjection of Ac-TZ14011, indicating a CXCR4-mediated accumulation in tumor. These findings suggested that 111In-DTPA-Ac-TZ14011 would be a potential agent for the imaging of CXCR4 expression in metastatic tumors in vivo.

Animals↗

PubMed2006

Release of vesicular Zn2+ in a rat transient middle cerebral artery occlusion model.

In the brain, Zn(2+) is stored in synaptic vesicles of a subgroup of glutamatergic nerve terminals. Although it has been reported that this Zn(2+) is released upon the excitation of nerves in vitro, there has been little study of the release of Zn(2+) during ischemia in vivo. Here, using brain microdialysis, the release of vesicular Zn(2+) was investigated in vivo. When the vesicular Zn(2+) was released into the synaptic cleft by a depolarizing stimulation achieved by perfusion with Ringer's solution containing high K(+) (100mM KCl), a significant increase in the extracellular concentration of Zn(2+) could be detected by microdialysis. Then, we investigated the release of vesicular Zn(2+) in a rat transient middle cerebral artery occlusion model using microdialysis. Consequently, the extracellular Zn(2+) level in the cortex increased within 15 min of the start of occlusion and reached a peak at 30 min, which was about twice the basal level. After 30 min, it declined with time returning to the basal level 15 min after reperfusion, which was performed after 60 min of occlusion. The results suggest that vesicular Zn(2+) would be released into the synaptic cleft during brain ischemia in vivo.

Animals↗

PubMed2006

Estimation of oxygen metabolism in a rat model of permanent ischemia using positron emission tomography with injectable15O-O2.

The threshold of cerebral blood flow (CBF) into infarction in rats has been indicated to be similar to that in patients. However, CBF does not reflect metabolic function, and so estimations of oxygen metabolism have been required. Here, we estimated changes in oxygen metabolism after occluding the right middle cerebral artery (MCA) in rats using an injectable (15)O-O(2) we developed. A decrease in CBF (left: 0.67+/-0.22 mL/min/g, right: 0.44+/-0.17 mL/min/g, P<0.05) and compensatory increase in the oxygen extraction fraction (OEF) (left: 0.42+/-0.13, right: 0.50+/-0.19, P<0.05) were observed at 1-h after occlusion. In contrast, a marked decrease in CBF and the cerebral metabolic rate for oxygen and a collapse of the compensatory OEF mechanism were found at 24 h after occlusion. Injectable (15)O-O(2) could be used to reliably estimate oxygen metabolism in an infarction rat model with positron emission tomography.

Animals↗

PubMed2006

Synthesis and evaluation of radioiodinated (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter.

PURPOSE: Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT. METHODS: (S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset. RESULTS: (S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT. CONCLUSION: These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.

Animals↗

PubMed2006

Protective effect of zinc against ischemic neuronal injury in a middle cerebral artery occlusion model.

In this study, we investigated the effect of vesicular zinc on ischemic neuronal injury. In cultured neurons, addition of a low concentration (under 100 microM) of zinc inhibited both glutamate-induced calcium influx and neuronal death. In contrast, a higher concentration (over 150 microM) of zinc decreased neuronal viability, although calcium influx was inhibited. These results indicate that zinc exhibits biphasic effects depending on its concentration. Furthermore, in cultured neurons, co-addition of glutamate and CaEDTA, which binds extra-cellular zinc, increased glutamate-induced calcium influx and aggravated the neurotoxicity of glutamate. In a rat transient middle cerebral artery occlusion (MCAO) model, the infarction volume, which is related to the neurotoxicity of glutamate, increased rapidly on the intracerebral ventricular injection of CaEDTA 30 min prior to occlusion. These results suggest that zinc released from synaptic vesicles may provide a protective effect against ischemic neuronal injury.

Animals↗

PubMed2006

Detection of maleate-induced Fanconi syndrome by decreasing accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice: a trial of separate evaluation of reabsorption.

OBJECTIVE: Fanconi syndrome is a renal dysfunction characterized by various combinations of renal tubular transport dysfunction involving amino acids, glucose, protein and other substances. Most reabsorption of amino acids occurs in proximal renal tubule segment 1 (S1). The present study evaluated the possibility of early detection of drug-induced Fanconi syndrome, based on decreased renal accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine (125I-IMT), an amino acid transport marker, in the S1 region of renal cortex. The present experimental model used maleate (MAL)-induced Fanconi syndrome in mice. Results were compared between 125I-IMT and 3 other clinical renal radiopharmaceuticals: 99mTc-2,3-dimercaptosuccinic acid (99mTc-DMSA); 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3); and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA). METHODS: Male ddY mice (age, 6 weeks; body weight, 25 g) were used to create a Fanconi model of renal dysfunction. A single dose of maleate disodium salt was administered by intraperitoneal injection (6 mmol/kg). Hematoxylin and eosin (HE) staining of the renal cortex, renal autoradiography and measurement of renal radioactivity of labeled compounds were performed at 30, 60, 90 and 120 min after MAL injection. At 5 min after injection of labeled compounds (18.5 kBq for accumulation experiment, 670 kBq for autoradiography), animals were sacrificed by ether overdose and kidneys were removed. For the accumulation experiment, radioactivity was measured using a well-type scintillation counter. For autoradiography, 20-microm sections of frozen kidney were used with Bio-Imaging Analyzer. RESULTS: At 30 min after MAL injection, HE staining showed pyknosis in some proximal tubule cells. At that time, accumulations of 125I-IMT and 99mTc-DMSA in the S1 region were approximately 67% and 55% of control levels (p < 0.005). MAL increased accumulation of 99mTc-DTPA in the S1 region, but had no effect on accumulation of 99mTc-MAG3 in the S 1 region. CONCLUSIONS: Decreased accumulation of 123I-IMT in the S1 region appears to represent a useful marker for detection of MAL-induced Fanconi syndrome. In future, we plan to assess the efficacy of using 125I-IMT to monitor renal dysfunction induced by nephrotoxic clinical drugs.

Absorption↗

PubMed2006

Change of central cholinergic receptors following lesions of nucleus basalis magnocellularis in rats: search for an imaging index suitable for the early detection of Alzheimer's disease.

Cholinergic system in the central nervous system is involved in the memory function. Thus, because the dysfunction of cholinergic system that project to the cerebral cortex from nucleus basalis of Meynert (nbM) would be implicated in the memory function deficits in Alzheimer's disease (AD), evaluating cholinergic function may be useful for the early detection of AD. In this study, because the nucleus basalis magnocellularis (NBM) in rats is equivalent to nbM in human, we investigated the change in cholinergic receptors in the frontal cortex of rats with unilateral lesion to the NBM to find an appropriate index for the early detection of AD using techniques of nuclear medicine. The right NBM was injected with ibotenic acid. [(18)F]FDG-PET images were obtained 3 days later. Some rats were sacrificed at 1 week, whereas others were subjected to a second [(18)F]FDG-PET at 4 weeks then sacrificed for membrane preparation. The prepared membranes were subjected to radioreceptor assays to measure the density of nicotinic and muscarinic acetylcholine receptors. Glucose metabolism had decreased on the damaged side compared to the control side at 3 days, but at 4 weeks, there was no difference between the sides. Nicotinic acetylcholine receptors had significantly decreased in density compared to the control side at both 1 and 4 weeks. However, muscarinic receptors were not affected. These results suggested that neuronal dysfunction in AD could be diagnosed at an early stage by imaging nicotinic acetylcholine receptors.

Alzheimer Disease↗

PubMed2006

Reduced 125I-meta-iodobenzylguanidine uptake and norepinephrine transporter density in the hearts of mice with MPTP-induced parkinsonism.

Uptake of (123)I-meta-iodobenzylguanidine ((123)I-MIBG) is markedly reduced in the hearts of patients with Parkinson's disease. Although the mechanism of this reduction is unclear, (12)(5)I-MIBG uptake is similarly reduced in the hearts of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP)-induced parkinsonism. Three groups of ten 15-week-old C57BL6 mice received intraperitoneal injections of (1) saline (control), (2) 10 mg/kg MPTP or (3) 40 mg/kg MPTP. After 0.185 MBq of (125)I-MIBG was injected, the percent injected dose of (125)I-MIBG per gram of tissue (%ID/g) was determined and cardiac concentrations of norepinephrine were measured. Cardiac concentrations of norepinephrine transporter (NET) were measured in three groups of twenty 15-week-old C57BL6 mice receiving these same treatments. The %ID/g in mice receiving 10 or 40 mg/kg MPTP (5.7 +/- 1.1 and 4.4 +/- 1.2%/g) was significantly lower than that in control mice (11.3 +/- 2.2%/g; P < .00001 and P < .0000001, respectively). The norepinephrine concentration in mice receiving 10 or 40 mg/kg MPTP (7.86 +/- 0.67 x 10(5) and 7.50 +/- 0.89 x 10(5) pg/wet g) was significantly lower than that in control mice (9.21 +/- 0.97 x 10(5) pg/wet g; P < .01 and P < .001, respectively). The NET density in mice receiving 10 or 40 mg/kg MPTP (81 +/- 12, 61 +/- 7 fmol/mg protein) was significantly lower than that in control mice (126 +/- 7 fmol/mg protein; P < .000001 and P < .0000001, respectively). The %ID/g of (125)I-MIBG and NET density decreased as the dose of MPTP increased. This study clearly shows that reduced cardiac (12)(5)I-MIBG uptake in mice with MPTP-induced parkinsonism is closely related to the reduced NET density in postganglionic cardiac sympathetic nerve terminals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2006

Synthesis and evaluation of radioiodinated cyclooxygenase-2 inhibitors as potential SPECT tracers for cyclooxygenase-2 expression.

UNLABELLED: Although several COX-2 inhibitors have recently been radiolabeled, their potential for imaging COX-2 expression remains unclear. In particular, the sulfonamide moiety of COX-2 inhibitors may cause slow blood clearance of the radiotracer, due to its affinity for carbonic anhydrase (CA) in erythrocytes. Thus, we designed a methyl sulfone-type analogue, 5-(4-iodophenyl)-1-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazole (IMTP). In this study, the potential of radioiodinated IMTP was assessed in comparison with a (125)I-labeled celecoxib analogue with a sulfonamide moiety ((125)I-IATP). METHODS: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation by hydrogen peroxide. The biodistribution of (125)I-IMTP and (125)I-IATP was determined by the ex vivo tissue counting method in rats. Distribution of the labeled compounds to rat blood cells was measured. RESULTS: The COX-2 inhibitory potency of IMTP (IC(50) = 5.16 microM) and IATP (IC(50) = 8.20 microM) was higher than that of meloxicam (IC(50) = 29.0 microM) and comparable to that of SC-58125 (IC(50) = 1.36 microM). The IC(50) ratios (COX-1/COX-2) indicated the high isoform selectivity of IMTP and IATP for COX-2. Significant levels of (125)I-IMTP and (125)I-IATP were observed in the kidneys and the brain (organs known to express COX-2). The blood clearance of (125)I-IMTP was much faster than that of (125)I-IATP. Distribution of (125)I-IATP to blood cells (88.0%) was markedly higher than that of (125)I-IMTP (18.1%), which was decreased by CA inhibitors. CONCLUSIONS: Our results showed a high inhibitory potency and selectivity of IMTP for COX-2. The substitution of a sulfonamide moiety to a methyl sulfone moiety effectively improved the blood clearance of the compound, indicating the loss of the cross reactivity with CA in (125)I-IMTP. (123)I-IMTP may be a potential SPECT radiopharmaceutical for COX-2 expression.

Animals↗

PubMed2006

Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation.

To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (186Re) that contains a hydroxyl group at the central carbon of its bisphosphonate structure, we attached a stable 186Re-MAMA chelate to the amino group of a 4-amino butylidene-bisphosphonate derivative [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-HBP) and we investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on affinity for hydroxyapatite and on biodistribution by conducting a comparative study with [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-BP). The precursor of 186Re-MAMA-HBP, trityl (Tr)-MAMA-HBP, was obtained by coupling a Tr-MAMA derivative to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. 186Re-MAMA-HBP was prepared by a reaction with 186ReO(4-) and SnCl2 in citrate buffer after the deprotection of the Tr groups of Tr-MAMA-HBP. After reversed-phase high-performance liquid chromatography, 186Re-MAMA-HBP had a radiochemical purity of over 95%. Compared with 186Re-MAMA-BP, 186Re-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into 186Re complex-conjugated bisphosphonates would be effective in enhancing accumulation in bones. These findings provide useful information on the design of bone-seeking therapeutic radiopharmaceuticals.

Animals↗

PubMed2006

In vivo measurement of presynaptic Zn2+ release during forebrain ischemia in rats.

Previous studies have suggested that during forebrain ischemia, considerable Zn2+ is released from synaptic vesicles of gultamatergic neuronal terminals and accumulates in hippocampal CA1 pyramidal neurons, leading to delayed neuronal death. However, since a time lag exists between the accumulation of Zn2+ and the occurrence of ischemia and there are conflicting reports about the amount of Zn2+ released, the level of released Zn2+ during ischemia in vivo is still unclear. In this study, we investigated the temporal change of extracellular Zn2+ in the hippocampal CA1 area using microdialysis and the accumulation of Zn2+ in hippocampal CA1 neurons with TSQ staining in rats with a transient forebrain ischemia. The level of extracellular Zn2+ in the CA1 area increased transiently reaching a peak 15 min after occlusion, then decreased with time, returning to the basal level 15 min after reperfusion. In addition, at this peak, the level of extracellular Zn2+ was about twice the basal level. Assessment of the intracellular Zn2+ in hippocampal neurons with TSQ revealed that Zn2+ accumulate at 24 h, but not 0 and 6 h after ischemia. These results suggest that, although the synaptic vesicular Zn2+ is released into the synaptic cleft during ischemia in vivo, the amount of released Zn2+ might not be so excessive, and it does not accumulate in hippocampal CA1 pyramidal neurons immediately after ischemia.

Animals↗

PubMed2006

A catheter-based intravascular radiation detector of vulnerable plaques.

UNLABELLED: Detection of vulnerable plaques before rupture is important in preventing acute coronary events such as myocardial infarction. Although therapeutic strategies such as percutaneous transluminal coronary angioplasty appear to prevent coronary occlusion and consequently may lead to improved prognosis in these patients, a method of detecting vulnerable plaques has not been established. A nuclear method that uses an intravascular radiation detector (IVRD) with the plaque-avid tracer (18)F-FDG is one of the most promising methods. The catheter-based IVRD consists of a catheter probe (a scintillator and flexible optic fibers), photomultipliers, a controller, and an automatic pullback unit and personal computer. A phantom study demonstrated that this detector was highly sensitive to (18)F and enabled the detection of (18)F point sources. However, details of the detection system in vivo remain unclear. METHODS: To evaluate vulnerable plaques in vivo, we investigated a canine femoral artery and coronary artery using this detector system. Our goal was to estimate the ability of this device to navigate through these arteries and to detect (18)F point sources fixed on their adventitia. RESULTS: In the study using a canine femoral artery, the IVRD could detect the point sources with good repeatability. In the study using an open-chest canine model, the catheter probe could easily be advanced into the left descending coronary artery, and the IVRD could detect target sources attached externally to the coronary artery (7- to 15-mm intervals) with good resolution. CONCLUSION: This newly developed catheter-based IVRD was able to detect, with good resolution, the slight radioactivity from (18)F point sources attached to the femoral artery and the coronary adventitia. These results show that catheter-based detection of coronary vulnerable plaques may be feasible.

Animals↗

PubMed2006

Application of 18F-FDG PET for monitoring the therapeutic effect of antiinflammatory drugs on stabilization of vulnerable atherosclerotic plaques.

UNLABELLED: The rupture of atherosclerotic vulnerable plaques and subsequent formation of thrombi are the main factors responsible for myocardial and cerebral infarctions. Because macrophage infiltration plays an essential role in plaque rupturing, pharmacologic therapy that reduces macrophage infiltration is required to stabilize the vulnerable plaques. The monitoring of therapeutic effect is important in assessing the therapeutic effects of drugs for individual patients. We previously reported that (18)F-FDG accumulates in macrophage-rich plaques. The present study was undertaken to investigate the usefulness of (18)F-FDG PET for monitoring therapies that target vascular inflammation. METHODS: Myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits were used in this study. The antioxidant probucol was included in the diet fed to 4 rabbits starting at 10 mo of age (probucol group). In a control study, 4 rabbits received standard rabbit chow (control group). (18)F-FDG PET experiments were performed on both groups before the study and at 1, 3, and 6 mo after treatment. After the last imaging session, the rabbits were sacrificed at 3 h after injection of (18)F-FDG, and the aortas were removed. The accumulated radioactivity was then measured, and the number of macrophages was determined by examination of stained sections. RESULTS: At the age of 10 mo, before the treatment, the aorta could be imaged by (18)F-FDG PET in all rabbits. The aorta could not be imaged after 6 mo of probucol treatment, whereas intense radioactivity was observed in the control rabbits throughout the investigation. The standardized uptake values (SUVs) of the aorta were decreased significantly in the probucol group after 3 mo of intervention as compared with the pretreatment period. The SUVs of the control group were increased gradually at 6 mo. Radioactivity in the aorta was significantly lower in the probucol group than that in the control group. Macrophages were already present at the beginning of the study, and probucol treatment for 6 mo resulted in a significant reduction of macrophage infiltration. CONCLUSION: (18)F-FDG PET was able to image the reduction of inflammation by probucol. (18)F-FDG PET should be useful for evaluating the therapeutic effect of drugs clinically and for the development of new drugs that can stabilize vulnerable plaques. (18)F-FDG PET should be useful for evaluating the therapeutic effect of drugs clinically and for the development of new drugs that can reduce inflammation of vulnerable plaques.

Animals↗

PubMed2006

Development of a novel 99mTc-chelate-conjugated bisphosphonate with high affinity for bone as a bone scintigraphic agent.

UNLABELLED: In bone scintigraphy using (99m)Tc with methylenediphosphonate ((99m)Tc-MDP) and hydroxymethylenediphosphonate ((99m)Tc-HMDP), it takes 2-6 h after an injection before imaging can start. This interval could be shortened with a new radiopharmaceutical with higher affinity for bone. Here, based on the concept of bifunctional radiopharmaceuticals, we designed a (99m)Tc-mercaptoacetylglycylglycylglycine (MAG3)-conjugated hydroxy-bisphosphonate (HBP) ((99m)Tc-MAG3-HBP) and a (99m)Tc-6-hydrazinopyridine-3-carboxylic acid (HYNIC)-conjugated hydroxy-bisphosphonate ((99m)Tc-HYNIC-HBP). METHODS: (99m)Tc-MAG3-HBP was prepared by complexation of MAG3-HBP with (99m)Tc using SnCl(2) as a reductant. The precursor of (99m)Tc-HYNIC-HBP, HYNIC-HBP, was obtained by deprotection of the Boc group after the coupling of Boc-HYNIC to a bisphosphonate derivative. (99m)Tc-HYNIC-HBP was prepared by a 1-pot reaction of HYNIC-HBP with (99m)TcO(4)(-), tricine, and 3-acetylpyridine in the presence of SnCl(2). Affinity for bone was evaluated in vitro by hydroxyapatite-binding assays for (99m)Tc-HMDP, (99m)Tc-MAG3-HBP, and (99m)Tc-HYNIC-HBP. Biodistribution experiments for the 3 (99m)Tc-labeled compounds were performed on normal rats. RESULTS: (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP were each prepared with a radiochemical purity of >95%. In the in vitro binding assay, (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP had greater affinity for hydroxyapatite than (99m)Tc-HMDP. In the biodistribution experiments, (99m)Tc-MAG3-HBP and (99m)Tc-HYNIC-HBP had higher levels of radioactivity in bone than (99m)Tc-HMDP. (99m)Tc-MAG3-HBP was cleared from the blood slower than (99m)Tc-HMDP, whereas there was no significant difference in clearance between (99m)Tc-HYNIC-HBP and (99m)Tc-HMDP. Consequently, (99m)Tc-HYNIC-HBP showed a higher bone-to-blood ratio than (99m)Tc-HMDP. CONCLUSION: We developed a novel (99m)Tc-chelate-conjugated bisphosphonate with high affinity for bone and rapid clearance from blood, based on the concept of bifunctional radiopharmaceuticals. The present findings indicate that (99m)Tc-HYNIC-HBP holds great potential for bone scintigraphy.

Animals↗