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ABSTRACT: This paper describes the synthesis and biological evaluation of styrylbenzimidazole (SBIM) derivatives as agents for imaging neurofibrillary tangles (NFT) in patients with Alzheimer's disease (AD). SBIM derivatives were prepared with 4-iodobenzene-1,2-diamine and substituted cinnamaldehydes. In binding experiments using recombinant tau and Aβ1-42 aggregates, SBIM-3 showed higher affinity for the tau aggregates than Aβ1-42 aggregates (ratio of Kd values was 2.73). In in vitro autoradiography and fluorescent staining, [(125)I]SBIM-3 (or SBIM-3) bound NFT in sections of AD brain tissue. In biodistribution experiments using normal mice, all [(125)I]SBIM derivatives showed high initial uptake into (3.20-4.11%ID/g at 2min after the injection) and rapid clearance from (0.12-0.33%ID/g at 60min after the injection) the brain. In conclusion, appropriate structural modifications of SBIM derivatives could lead to more useful agents for the in vivo imaging of NFT in AD brains.
Bioorganic & medicinal chemistry 03/2013; · 2.82 Impact Factor
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ABSTRACT: Background: Therapeutic peptides and proteins are being increasingly explored as potential therapeutic agents for molecular-targeted therapy, and the requirement for quantitative bioanalytical tools for such molecules has been discussed. Results: The distribution of octreotide, a synthetic octapeptide analog of somatostatin, in the liver and kidney of mice administered with the analog was clearly visualized by MALDI-Imaging MS (IMS). The developed MALDI-IMS analytical method successfully quantified the amount of octreotide on tissue sections (accuracy was 76-127%) and the 2,5-dihydroxybenzoic acid-based normalization method was effective. Conclusion: The results of this study suggest that MALDI-IMS enables the quantification of an administered therapeutic peptide on biological tissue sections, as well as visualization of the in vivo distribution of the peptide.
Bioanalysis 03/2013; 5(5):603-12. · 3.22 Impact Factor
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ABSTRACT: Since membrane type-1 matrix metalloproteinase (MT1-MMP) plays pivotal roles in tumor progression and metastasis and holds great promise as an early biomarker for malignant tumors, a method of evaluating MT1-MMP expression levels would be valuable for molecular biological and clinical studies. Although we have previously developed a (99m) Tc-labeled anti-MT1-MMP monoclonal IgG ((99m) Tc-MT1-mAb) as an MT1-MMP imaging probe by nuclear medical techniques for this purpose, slow pharmacokinetics were a problem due to its large molecular size. Thus, in this study, our aim was to develop miniaturized antibodies, a single chain antibody fragment (MT1-scFv) and a dimer of two molecules of scFv (MT1-diabody), as the basic structures of MT1-MMP imaging probes followed by in vitro and in vivo evaluation with an (111) In radiolabel. Phage display screening successfully provided MT1-scFv and MT1-diabody, which had sufficiently high affinity for MT1-MMP (K(D) =29.8 and 17.1 nM). Both (111) In labeled miniaturized antibodies showed higher uptake in MT1-MMP expressing HT1080 cells than in non-expressing MCF7 cells. An in vivo biodistribution study showed rapid pharmacokinetics for both probes, which exhibited greater than 20 fold higher tumor to blood radioactivity ratios (T/B ratio), an index for in vivo imaging, than (99m) Tc-MT1-mAb 6 h post-administration, and significantly higher tumor accumulation in HT1080 than MCF7 cells. SPECT images showed heterogeneous distribution and ex vivo autoradiographic analysis revealed that the radioactivity distribution profiles in tumors corresponded to MT1-MMP-positive areas. These findings suggest that the newly developed miniaturized antibodies are promising probes for detection of MT1-MMP in cancer cells.
Cancer Science 01/2013; · 3.33 Impact Factor
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ABSTRACT: On the basis of the findings obtained by X-ray crystallography of Ga-DOTA chelates and the drug design concept of bifunctional radiopharmaceuticals, we previously designed and synthesized a radiogallium-labeled DOTA chelate containing two metronidazole moieties, (67)Ga-DOTA-MN2, for hypoxic tumor imaging. As expected, (67)Ga-DOTA-MN2 exhibited high in vivo stability, although two carboxyl groups in the DOTA skeleton were conjugated with metronidazole moieties. In this study, we evaluated (67/68)Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors. (67)Ga-labeling of DOTA-MN2 with (67)GaCl3 was achieved with high radiochemical yield (>85%) by 1-min of microwave irradiation (50 W). The pharmacokinetics of (67)Ga-DOTA-MN2 were examined in FM3A tumor-bearing mice, and compared with those of (67)Ga-DOTA-MN1 containing one metronidazole unit and (67)Ga-DOTA. Upon administration, (67)Ga-DOTA-MN2 exhibited higher accumulation in the implanted tumors than (67)Ga-DOTA. Tumor-to-blood ratios of (67)Ga-DOTA-MN2 were about two-fold higher than those of (67)Ga-DOTA-MN1. Autoradiographic analysis showed the heterogeneous localization of (67)Ga-DOTA-MN2 in the tumors, which corresponds to hypoxic regions suggested by well-established hypoxia marker drug, pimonidazole. Furthermore, in positron emission tomography (PET) study, the tumors of mice administered (68)Ga-labeled DOTA-MN2 were clearly imaged by small-animal PET at 1 h after administration. This study demonstrates the potential usefulness of (67/68)Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors and suggests that two functional moieties, such as metronidazole, can be conjugated to radiogallium-DOTA chelate without reducing the complex stability. The present findings provide useful information about the chemical design of radiogallium-labeled radiopharmaceuticals for PET and single photon emission computed tomography (SPECT) studies.
Biological & Pharmaceutical Bulletin 01/2013; 36(4):602-8. · 1.66 Impact Factor
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Zijing Li,
Mengchao Cui,
Jiapei Dai,
Xuedan Wang,
Pingrong Yu,
Yanping Yang,
Jianhua Jia,
Hualong Fu,
Masahiro Ono,
Hongmei Jia, Hideo Saji,
Bo-Li Liu
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ABSTRACT: Rhenium and technetium-99m cyclopentadienyl tricarbonyl complexes mimicking the chalcone structure were prepared. These complexes were proved to have affinity to β-amyloid (Aβ) in fluorescent staining on brain sections of Alzheimer's Disease (AD) patient and binding assay using Aβ1-42 aggregates, with Ki values ranging from 899 to 108 nM as the extension of conjugated π system. In vitro autoradiograpy on sections of transgenic mouse brain confirmed the affinity of [(99m)Tc]5 (Ki = 108 nM). In biodistribution, all compounds showed good initial uptakes into the brain and fast blood clearance, while the decreasing of initial brain uptakes correspond to increasing of conjugation length, from 4.10 ± 0.38 % ID/g ([(99m)Tc]3) to 1.11 ± 0.34 % ID/g ([(99m)Tc]5). These small technetium-99m complexes (< 500 Da) designed by an integrated approach provide encouraging evidence that development of a promising (99m)Tc-labeled agent for imaging Aβ plaques in the brain may be feasible.
Journal of Medicinal Chemistry 12/2012; · 4.80 Impact Factor
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ABSTRACT: INTRODUCTION: Despite the significant effort in developing radioprobes for atherosclerosis, few have low molecular weight. Oxidized LDL (OxLDL), a highly proinflammatory and proatherogenic factor that is abundant in atherosclerotic plaques, plays a pivotal role in plaque destabilization, which makes OxLDL a relevant probe target. We developed a radioiodinated short peptide, AHP7, as a low molecular weight probe for specific OxLDL imaging and evaluated its utility using myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits (WHHLMI). METHODS: [(125)I]AHP7 was designed and synthesized based on the sequence of Asp-hemolysin, an OxLDL binding protein extracted from Aspergillus fumigatus. In vitro binding studies with OxLDL having varying degrees of oxidation were performed. Radioactivity accumulation in the aorta was measured 30min post-administration in rabbits. Autoradiography and histological studies were performed using serial aorta sections. A radioiodinated scrambled peptide ([(125)I]AHP scramble) was used as a negative control. RESULTS: [(125)I]AHP7 bound to OxLDL in proportion to the degree of oxidation (R=0.91, P<0.0001) and was inhibited by unlabeled AHP7 in a concentration-dependent manner. The aorta accumulation level and aorta/blood and aorta/muscle ratios of [(125)I]AHP7 in WHHLMI were 2.8-, 1.3- and 1.8-fold higher, respectively, than those in control rabbits (P<0.001). Co-administration of AHP7 significantly reduced [(125)I]AHP7 radioactivity in aorta sections (P<0.0001). Regional radioactivity levels in the aorta sections showed nonuniformity but similarity to the immunohistochemical OxLDL density. CONCLUSIONS: The potential of radioiodinated AHP7 for selectively imaging OxLDL was demonstrated both in vitro and in vivo.
Nuclear Medicine and Biology 11/2012; · 3.02 Impact Factor
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Mengchao Cui,
Xuedan Wang,
Pingrong Yu,
Jinming Zhang,
Zijing Li,
Xiaojun Zhang,
Yanping Yang,
Masahiro Ono,
Hongmei Jia, Hideo Saji,
Boli Liu
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ABSTRACT: A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for (18)F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [(18)F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([(18)F]32) (K(i) = 8.0 ± 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [(18)F]32 to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [(18)F]32 is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.
Journal of Medicinal Chemistry 09/2012; · 4.80 Impact Factor
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Pingrong Yu,
Mengchao Cui,
Xuedan Wang,
Xiaojun Zhang,
Zijing Li,
Yanping Yang,
Jianhua Jia,
Jinming Zhang,
Masahiro Ono, Hideo Saji,
Hongmei Jia,
Boli Liu
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ABSTRACT: In continuation of our study on the 2-phenylquinoxaline scaffold as potential β-amyloid imaging probes, two [(18)F]fluoro-pegylated 2-phenylquinoxaline derivatives, 2-(4-(2-[(18)F]fluoroethoxy)phenyl)-N-methylquinoxalin-6-amine ([(18)F]4a) and 2-(4-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)phenyl)-N-methylquinoxalin-6-amine ([(18)F]4b) were prepared. Both of them displayed high binding affinity to Aβ(1-42) aggregates (K(i) = 10.0 ± 1.4 nM for 4a, K(i) = 5.3 ± 3.2 nM for 4b). The specific and high binding of [(18)F]4a and [(18)F]4b to Aβ plaques was confirmed by in vitro autoradiography on brain sections of AD human and transgenic mice. In biodistribution in normal mice, [(18)F]4a displayed high initial brain uptake (8.17% ID/g at 2 min) and rapid washout from the brain. These preliminary results suggest [(18)F]4a may be a potential PET imaging agent for Aβ plaques in the living human brain.
European journal of medicinal chemistry 09/2012; 57C:51-58. · 3.27 Impact Factor
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ABSTRACT: Recently, the requirement for a quantitative research method using imaging mass spectrometry (IMS) to be developed has been discussed. Specifically, the simultaneous quantification of a drug in multiple organs by using whole-body sections could be insightful for the pharmaceutical industry in the study of drug distribution.
Frozen whole-body sections were obtained from mice injected with raclopride, a dopamine D2 receptor selective antagonist, and coated with a matrix-assisted laser desorption/ionization (MALDI) matrix compound. The whole-body sections were then analyzed using a linear ion trap mass spectrometer equipped with a MALDI source. The concentration of raclopride in each tissue was determined using liquid chromatography/tandem mass spectrometry (LC/MS/MS).
The IMS-based signal intensity of raclopride strongly correlated with the concentration of the drug in the tissue samples (R=0.94; p <0.001) of six different organs. Furthermore, the spatial information obtained by IMS was very similar to that obtained by autoradiography, which is a traditional technique used for the study of drug distribution.
This study suggests that IMS enables the quantitative analysis of drug distribution in multiple organs simultaneously. In addition, it enhances ideal drug candidate selection in terms of efficient evaluations.
Rapid Communications in Mass Spectrometry 07/2012; 26(13):1549-56. · 2.79 Impact Factor
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ABSTRACT: This letter describes the synthesis and biological evaluation of a novel series of radioiodinated oxindole (OI) derivatives for detecting neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer's disease (AD). In binding experiments in vitro, 2-oxindole (2-OI) and 3-oxindole (3-OI) derivatives showed affinity for tau aggregates. The 3-OI derivative 14 showed the highest affinity of these derivatives. In biodistribution experiments using normal mice, the OI derivatives displayed good uptake (2.4-2.5%ID/g at 2 min) and clearance from the brain with time (0.6-1.4%ID/g at 30 min). In fluorescence staining experiments using AD brain sections, 14 clearly stained NFTs. 3-OI may serve as a new molecular scaffold for developing novel NFT imaging agents.
Bioorganic & medicinal chemistry letters 07/2012; 22(17):5700-3. · 2.65 Impact Factor
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Mengchao Cui,
Masahiro Ono,
Hiroyuki Kimura,
Masashi Ueda,
Yuji Nakamoto,
Kaori Togashi,
Yoko Okamoto,
Masafumi Ihara,
Ryosuke Takahashi,
Boli Liu, Hideo Saji
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ABSTRACT: Two radiofluoro-pegylated phenylbenzoxazole derivatives, 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N-methylaniline ([(18)F]24) and 4-(5-(2-(2-(2-[(18)F]fluoroethoxy)ethoxy)ethoxy)benzo[d]oxazol-2-yl)-N,N-dimethylaniline ([(18)F]32), were synthesized and evaluated as probes for imaging cerebral β-amyloid (Aβ) plaques in living brain tissue by PET. [(18)F]24 and [(18)F]32 displayed high affinity for Aβ(1-42) aggregates (K(i) = 9.3 and 3.9 nM, respectively). In vitro autoradiography with sections of post-mortem AD brain and transgenic mouse brain confirmed the affinity of these tracers. Initial high uptake into and rapid washout from the brain in normal mice were observed. [(18)F]24 also displayed excellent binding to Aβ plaques in ex vivo autoradiographic experiments with Tg2576 mice. Furthermore, small-animal PET studies demonstrated significant differences in the clearance profile after the administration of [(18)F]24 between Tg2576 and wild-type mice. The results suggest [(18)F]24 to be a useful PET agent for detecting Aβ plaques in the living human brain.
Journal of Medicinal Chemistry 06/2012; · 4.80 Impact Factor
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ABSTRACT: PurposeAlthough 15O-O2 gas inhalation can provide a reliable and accurate myocardial metabolic rate for oxygen by PET, the spillover from gas volume
in the lung distorts the images. Recently, we developed an injectable method in which blood takes up 15O-O2 from an artificial lung, and this made it possible to estimate oxygen metabolism without the inhalation protocol. In the
present study, we evaluated the effectiveness of the injectable 15O-O2 system in porcine hearts.
MethodsPET scans were performed after bolus injection and continuous infusion of injectable 15O-O2 via a shunt between the femoral artery and the vein in normal pigs. The injection method was compared to the inhalation method.
The oxygen extraction fraction (OEF) in the lateral walls of the heart was calculated by a compartmental model in view of
the spillover and partial volume effect.
ResultsA significant decrease of lung radioactivity in PET images was observed compared to the continuous inhalation of 15O-O2 gas. Furthermore, the injectable 15O-O2 system provides a measurement of OEF in lateral walls of the heart that is similar to the continuous-inhalation method (0.71 ± 0.036
and 0.72 ± 0.020 for the bolus-injection and continuous-infusion methods, respectively).
ConclusionThese results indicate that injectable 15O-O2 has the potential to evaluate myocardial oxygen metabolism.
European journal of nuclear medicine and molecular imaging 04/2012; 37(2):377-385. · 4.99 Impact Factor
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ABSTRACT: We designed and synthesized a BODIPY-based probe (BAP-1) for the imaging of β-amyloid plaques in the brain. In binding experiments in vitro, BAP-1 showed excellent affinity for synthetic Aβ aggregates. β-Amyloid plaques in Tg2576 mouse brain were clearly visualized with BAP-1. In addition, the labeling of β-amyloid plaques was demonstrated in vivo in Tg2576 mice. These results suggest BAP-1 to be a useful fluorescent probe for the optical imaging of cerebral β-amyloid plaques in patients with Alzheimer's disease.
ACS Chemical Neuroscience 04/2012; 3(4):319-24. · 3.68 Impact Factor
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ABSTRACT: Objective: We investigated mechanisms of renal accumulation of radioiodinated 3-iodo-α-methyl-L-tyrosine (IMT), which has been used
clinically for tumor imaging and as an amino acid transport marker in studies of brain and pancreas function.Methods: In this study, we used125I- or123I-labeled IMT ([125I]IMT or [123I]IMT) as the transport marker. Partition coefficients of [125I]IMT were determined for hypothetic urine at pH ranging from 5 to 8. The examination of uptake and inhibition of [125I]IMT was performed using normal human renal proximal tubule epithelial cells (RPTEC), which are characteristic of the proximal
convoluted tubule. The plasma protein binding ratio of [125I]IMT was determined using rats. In thein vivo experiments using mice, we examined biodistribution and excretion inhibition, and performed whole body autoradiography. Also,
renal SPECT using [123I]IMT was performed using a normal canine.Results: Very low lipophilicity of [125I]IMT in hypothetic urine suggests that a carrier-mediated pathway contributes to its marked kidney accumulation. [125I]IMT uptake into RPTEC was significantly inhibited by 2-amino-bicyclo[2,2,l]heptane-2-carboxylic acid (BCH) in a sodium-dependent
manner, suggesting reab-sorption mainly via system B° in apical membrane of proximal tubule. Plasma protein binding ratio
of IMT was 45.4 ± 5.6%. At 6 hr after administration of IMT to mice, excretion via urinary tract was 77.51% of injected dose,
and excretion into feces was 0.25%. Furosemide, ethacrynic acid and probenecid inhibited tubular secretion of [125I]IMT in mice. We obtained very clear autoradio-graphs of mouse renal cortex and a canine renal SPECT image (S2-like region).Conclusions: We believe that [123I]IMT is useful for kidney imaging. In future studies, we plan to examine the use of [123I]IMT in diagnosis of disease.
Annals of Nuclear Medicine 04/2012; 18(3):263-270. · 1.50 Impact Factor
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ABSTRACT: The retention mechanism of the novel imaging/radiotherapeutic agent, Cu-diacetyl-bis(N
4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells was clarified in comparison with that in normal tissuein vitro. With Cu-ATSM and reversed phase HPLC analysis, the reductive metabolism of Cu-ATSM in subcellular fractions obtained from
Ehrlich ascites tumor cells was examined. As a reference, mouse brain was used. To determine the contribution of enzymes in
the retention mechanisms, and specific inhibitor studies were performed. In subcellular fractions of tumor cells, Cu-ATSM
was reduced mainly in the microsome/cytosol fraction rather than in the mitochondria. This finding was completely different
from that found in normal brain cells. The reduction process in the microsome/cytosol was heat-sensitive and enhanced by adding
exogenous NAD(P)H, an indication of enzymatic reduction of Cu-ATSM in tumor cells. Among the known bioreductive enzymes. NADH-cytochrome
b5 reductase and NADPH-cytochrome P450 reductase in microsome played a major role in the reductive retention of Cu-ATSM in
tumors. This enzymatic reduction was enhanced by the induction of hypoxia. Radiocopper labeled Cu-ATSM provides useful information
for the detection of hypoxia as well as the microsomal bioreductive enzyme expression in tumor.
Annals of Nuclear Medicine 04/2012; 15(6):499-504. · 1.50 Impact Factor
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ABSTRACT: Three novel (99m)Tc-labeled pyridyl benzofuran derivatives were tested as potential probes for imaging β-amyloid plaques using single photon emission computed tomography (SPECT). The (99m)Tc and corresponding rhenium complexes were synthesized with bis(aminoethanethiol) (BAT) as a chelating ligand. All Re complexes showed affinity for Aβ(1-42) aggregates (K(i) = 13.6-149.6 nM). Biodistribution experiments in normal mice revealed that the (99m)Tc-labeled derivatives displayed sufficient uptake in the brain (1.41-1.80% ID/g at 2 min postinjection). Notably, [(99m)Tc]BAT-Bp-2 showed a good initial uptake (1.80% ID/g at 2 min) and a reasonable washout from the brain (0.79% ID/g at 60 min). Ex vivo autoradiography with [(99m)Tc]BAT-Bp-2 revealed substantial labeling of β-amyloid plaques in sections of brain tissue from Tg2576 transgenic mice but not in the age-matched controls. [(99m)Tc]BAT-Bp-2 may be a potential SPECT probe for imaging β-amyloid plaques in Alzheimer's brains.
Journal of Medicinal Chemistry 03/2012; 55(5):2279-86. · 4.80 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease of the brain associated with irreversible cognitive decline, memory impairment, and behavioral changes. Postmortem brains of AD patients reveal neuropathologic features, in particular the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), which contain β-amyloid peptides and highly phosphorylated tau proteins. Currently, AD can only be definitively confirmed by postmortem histopathologic examination of SPs and NFTs in the brain. Therefore, SPs and NFTs in the brain may be useful as biomarkers for the differential diagnosis of AD; the detection of individual SPs and NFTs in vivo by positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) should improve diagnosis and also accelerate discovery of effective therapeutic agents for AD. Many PET/SPECT imaging probes for SPs have already been developed. Several of the PET probes have been shown in clinical trials to be useful for the imaging of β-amyloid plaques in living brain tissue. More recently, the development of PET/SPECT probes for in vivo imaging of NFTs is an active area of study in the field of molecular imaging because the appearance of NFT pathology correlates well with clinical severity of dementia. We will review current research on the development of PET/SPECT imaging probes for in vivo detection of SPs and NFTs and their application to diagnosis and therapy of AD.
Journal of Pharmacological Sciences 03/2012; 118(3):338-44. · 2.08 Impact Factor
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ABSTRACT: We investigated the biodistribution of arginine-rich cell-penetrating peptides (CPPs) in tumor-xenografted nude mice after intravenous injection of fluorescently labeled CPPs using in vivo imaging. The CPPs used included HIV-1 Tat (48-60), penetratin, and the L- and D-enantiomers of oligoarginines (8, 12, and 16 residues), all of which are reported to have high cell penetration. Among the tested peptides, high accumulation in tumors was observed for the D-form of octaarginine (r8), and glycosaminoglycans played a key role. Injection of an r8-doxorubicin conjugate (4mg doxorubicin/kg) effectively suppressed tumor proliferation, with no significant decrease in mouse weight, whereas administration of doxorubicin itself (6mg/kg), yielding a similar degree of tumor-growth suppression, resulted in significant weight loss. These results suggest the potential of r8 as a prototypic tumor-targeting vector.
Journal of Controlled Release 01/2012; 159(2):181-8. · 5.73 Impact Factor
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ABSTRACT: Cardiovascular disease is the leading cause of death worldwide. Unstable atherosclerotic plaques are prone to rupture followed by thrombus formation, vessel stenosis, and occlusion and frequently lead to acute myocardial infarction and brain infarction. As such, unstable plaques represent an important diagnostic target in clinical settings and the specific diagnosis of unstable plaques would enable preventive treatments for cardiovascular disease. To date, various imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and intravascular ultrasound (IVUS) have been widely used clinically. Although these methods have advantages in terms of spatial resolution and the ability to make detailed identification of morphological alterations such as calcifications and vessel stenosis, these techniques require skill or expertise to discriminate plaque instability, which is essential for early diagnosis and treatment and can present difficulties for quantitative estimation. On the other hand, nuclear imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) can noninvasively collect quantitative information on the expression levels of functional molecules and metabolic activities in vivo and thus provide functional diagnoses of unstable plaques with high sensitivity. Specifically, unstable plaques are characterized by an abundance of invasive inflammatory cells (macrophages), increased oxidative stress that increases oxidized LDL and its receptor expressed on cells in the lesions, increased occurrence of apoptosis of macrophages and other cells involved in disease progression, increased protease expression and activity, and finally thrombus formation triggered by plaque rupture, which is the most important mechanism leading to the onset of infarctions and ischemic sudden death. Therefore, these characteristics can all be targets for molecular imaging by PET and SPECT. In this paper, we review the present state and future of radiolabelled probes that have been developed for detecting atherosclerotic unstable plaques with nuclear imaging techniques.
American journal of nuclear medicine and molecular imaging. 01/2012; 2(4):432-47.
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ABSTRACT: (99m)Tc-tricarbonyl [(99m)Tc(CO)(3)] complexes have been conventionally synthesized by heating [(99m)Tc(CO)(3)(H(2)O)(3)](+) and a tridentate chelating ligand under atmospheric pressure; however, this method is poor in terms of chemical yield and reproducibility. Moreover, since the half-life of (99m)Tc is very short (6 h), the development of facile and rapid methods of synthesizing (99m)Tc-labeled compounds, which could be used as radioactive tracers for single photon emission computed tomography (SPECT), is required. Thus, we initiated a study on the application of a microwave reaction to the synthesis of (99m)Tc(CO)(3)-2-picolylamine monoacetic acid (PAMA) [(99m)Tc(CO)(3)-PAMA] complexes on the basis of the fact that synthesis of metal complexes proceeds rapidly by microwave irradiation owing to an efficient exothermic phenomenon and heat conduction effect. Formation of by-products could be markedly suppressed by comparison with that in conventional methods. In the present study, rhenium (Re), an element belonging to the same group in the periodic table as technetium (Tc), and which also forms bipyramidal complexes, was first used to investigate the synthetic reaction because no stable isotopes exist for Tc. As a result, when water was used as the solvent under the irradiation of microwaves within 1 min, the Re(CO)(3)-PAMA complex could be directly synthesized from ethyl ester of PAMA (PAMAEE) and [Re(CO)(3)(H(2)O)(3)]Br in one step and with a high yield (94%). Finally, the (99m)Tc(CO)(3)-PAMA complex was successfully synthesized at a high radiochemical yield (>99%) within 1 min of reaction using (99m)Tc instead of Re under the same conditions.
Chemical & pharmaceutical bulletin 01/2012; 60(1):79-85. · 1.70 Impact Factor
