Search tips
Search criteria

Results 1-5 (5)

Clipboard (0)

Select a Filter Below

more »
Year of Publication
Document Types
1.  PET Quantification of Cerebral Oxygen Metabolism in Small Animals 
The Scientific World Journal  2014;2014:159103.
Understanding cerebral oxygen metabolism is of great importance in both clinical diagnosis and animal experiments because oxygen is a fundamental source of brain energy and supports brain functional activities. Since small animals such as rats are widely used to study various diseases including cerebral ischemia, cerebrovascular diseases, and neurodegenerative diseases, the development of a noninvasive in vivo measurement method of cerebral oxygen metabolic parameters such as oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) as well as cerebral blood flow (CBF) and cerebral blood volume (CBV) has been a priority. Although positron emission tomography (PET) with 15O labeled gas tracers has been recognized as a powerful way to evaluate cerebral oxygen metabolism in humans, this method could not be applied to rats due to technical problems and there were no reports of PET measurement of cerebral oxygen metabolism in rats until an 15O-O2 injection method was developed a decade ago. Herein, we introduce an intravenous administration method using two types of injectable 15O-O2 and an 15O-O2 gas inhalation method through an airway placed in the trachea, which enables oxygen metabolism measurements in rats.
PMCID: PMC4151541  PMID: 25202714
2.  Investigation of cyanine dyes for in vivo optical imaging of altered mitochondrial membrane potential in tumors 
Cancer Medicine  2014;3(4):775-786.
Mitochondrial membrane potential (Δψm) alteration is an important target for cancer diagnosis. In this study, we designed a series of near-infrared fluorescent cationic cyanine dyes with varying alkyl chain lengths (IC7-1 derivatives) to provide diverse lipophilicities and serum albumin-binding rates, and we evaluated the usefulness of these derivatives for in vivo Δψm imaging. IC7-1 derivatives with side chains from methyl to hexyl (IC7-1-Me to IC7-1-He) were synthesized, and their optical properties were measured. Cellular uptake and intracellular distribution were investigated with depolarized HeLa cells from carbonyl cyanine m-chlorophenylhydrazone (CCCP) treatment using a spectrofluorometer and a fluorescence microscope. Serum albumin-binding rates were evaluated using albumin-binding inhibitors. In vivo optical imaging was performed with HeLa cell xenograft mice following intravenous administration of IC7-1 derivatives with or without warfarin and CCCP as in vivo blocking agents. IC7-1 derivatives showing maximum excitation and emission wavelengths at 823 nm and ∼845 nm, respectively, were synthesized. IC7-1-Me to -Bu showed fluorescence in mitochondria that decreased with CCCP treatment in a concentration-dependent manner, which showed that IC7-1-Me to -Bu successfully indicated Δψm. Tumors were clearly visualized after IC7-1-Bu administration. Treatment with warfarin or CCCP significantly decreased IC7-1-Bu fluorescence in the tumor region. In summary, IC7-1-Bu exhibited fluorescence localized to mitochondria dependent on Δψm, which enabled clear in vivo tumor imaging via serum albumin as a drug carrier for effective tumor targeting. Our data suggest that IC7-1-Bu is a promising NIR probe for in vivo imaging of the altered Δψm of tumor cells.
PMCID: PMC4303146  PMID: 24737784
Albumin binding; cancer diagnosis; mitochondrial membrane potential; near infrared; optical imaging
3.  Investigation of a MMP-2 Activity-Dependent Anchoring Probe for Nuclear Imaging of Cancer 
PLoS ONE  2014;9(7):e102180.
Since matrix metalloproteinase-2 (MMP-2) is an important marker of tumor malignancy, we developed an original drug design strategy, MMP-2 activity dependent anchoring probes (MDAP), for use in MMP-2 activity imaging, and evaluated the usefulness of this probe in in vitro and in vivo experiments.
We designed and synthesized MDAP1000, MDAP3000, and MDAP5000, which consist of 4 independent moieties: RI unit (111In hydrophilic chelate), MMP-2 substrate unit (short peptide), anchoring unit (alkyl chain), and anchoring inhibition unit (polyethylene glycol (PEGn; where n represents the approximate molecular weight, n = 1000, 3000, and 5000). Probe cleavage was evaluated by chromatography after MMP-2 treatment. Cellular uptake of the probes was then measured. Radioactivity accumulation in tumor xenografts was evaluated after intravenous injection of the probes, and probe cleavage was evaluated in tumor homogenates.
MDAP1000, MDAP3000, and MDAP5000 were cleaved by MMP-2 in a concentration-dependent manner. MDAP3000 pretreated with MMP-2 showed higher accumulation in tumor cells, and was completely blocked by additional treatment with an MMP inhibitor. MDAP3000 exhibited rapid blood clearance and a high tumor accumulation after intravenous injection in a rodent model. Furthermore, pharmacokinetic analysis revealed that MDAP3000 exhibited a considerably slow washout rate from tumors to blood. A certain fraction of cleaved MDAP3000 existed in tumor xenografts in vivo.
The results indicate the possible usefulness of our MDAP strategy for tumor imaging.
PMCID: PMC4092090  PMID: 25010662
4.  Development of a Radioiodinated Triazolopyrimidine Probe for Nuclear Medical Imaging of Fatty Acid Binding Protein 4 
PLoS ONE  2014;9(4):e94668.
Fatty acid binding protein 4 (FABP4) is the most well-characterized FABP isoform. FABP4 regulates inflammatory pathways in adipocytes and macrophages and is involved in both inflammatory diseases and tumor formation. FABP4 expression was recently reported for glioblastoma, where it may participate in disease malignancy. While FABP4 is a potential molecular imaging target, with the exception of a tritium labeled probe there are no reports of other nuclear imaging probes that target this protein. Here we designed and synthesized a nuclear imaging probe, [123I]TAP1, and evaluated its potential as a FABP4 targeting probe in in vitro and in vivo assays. We focused on the unique structure of a triazolopyrimidine scaffold that lacks a carboxylic acid to design the TAP1 probe that can undergo facilitated delivery across cell membranes. The affinity of synthesized TAP1 was measured using FABP4 and 8-anilino-1-naphthalene sulfonic acid. [125I]TAP1 was synthesized by iododestannylation of a precursor, followed by affinity and selectivity measurements using immobilized FABPs. Biodistributions in normal and C6 glioblastoma-bearing mice were evaluated, and excised tumors were subjected to autoradiography and immunohistochemistry. TAP1 and [125I]TAP1 showed high affinity for FABP4 (Ki = 44.5±9.8 nM, Kd = 69.1±12.3 nM). The FABP4 binding affinity of [125I]TAP1 was 11.5- and 35.5-fold higher than for FABP3 and FABP5, respectively. In an in vivo study [125I]TAP1 displayed high stability against deiodination and degradation, and moderate radioactivity accumulation in C6 tumors (1.37±0.24% dose/g 3 hr after injection). The radioactivity distribution profile in tumors partially corresponded to the FABP4 positive area and was also affected by perfusion. The results indicate that [125I]TAP1 could detect FABP4 in vitro and partly in vivo. As such, [125I]TAP1 is a promising lead compound for further refinement for use in in vivo FABP4 imaging.
PMCID: PMC3986099  PMID: 24732569
5.  Radiolabelled probes for imaging of atherosclerotic plaques 
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.
PMCID: PMC3484420  PMID: 23145360
Molecular imaging; atherosclerosis; plaque; positron emission tomography; single photon emission computed tomography; 2-[18F]Fluoro-2-deoxy-D-glucose; lectin-like oxidized low density lipoprotein receptor-1; apoptosis; matrix metalloproteinase; thrombus

Results 1-5 (5)