Yasuhiko Iida

Phosphorescent light-emitting iridium complexes serve as a hypoxia-sensing probe for tumor imaging in living animals.

Iridium complex is a promising organic light-emitting diode material for next generation video displays that emits phosphorescence quenched by oxygen. We used this oxygen-quenching feature for imaging tumor hypoxia. Red light-emitting Ir(btp)(2)(acac) (BTP) presented hypoxia-dependent light emission in culture cell lines, whose intensity was in parallel with hypoxia-inducible factor-1alpha images. BTP was further applied to imaging five nude mouse transplanted with tumors. All tumors presented a bright BTP-emitting image even 5 minutes after injection. The minimal image recognition size was approximately 2 mm in diameter. By morphologic examination and phosphorescence lifetime measurement, BTP appeared to localize to the tumor cells. Because BTP is easily modifiable, we synthesized BTP analogues with a longer excitation/emission wavelength. One of them, BTPHSA, depicted clear imaging from tumors transplanted 6 to 7 mm deep from the skin surface. We suggest that iridium complex materials have a vast potential for imaging hypoxic lesions such as tumor tissues.

PET and PET/CT using 18F-FDG in the diagnosis and management of cancer patients

Positron emission tomography (PET) using 2-18F-fluoro-2-deoxy-D-glucose (FDG), a radioactive derivative of glucose, is an advanced imaging tool, based on the increased glucose consumption of cancer cells. FDG-PET provides information that is not obtainable with other imaging modalities, and is very effective in the diagnosis and management of patients with various types of cancers. However, there are some limitations, such as low FDG uptake in some cancers, substantial FDG uptake in inflammatory cells, and the lack of anatomical information and poor imaging quality of PET. A recently developed integrated PET/computed tomography (CT) system, which combines a PET camera and CT scanner in a single session, has overcome these drawbacks by providing both anatomical and functional imaging at the same position. PET and/or PET/CT using FDG is clinically useful in the detection of cancer, the differentiation of malignant and benign lesions, the staging of cancer before therapy, and the assessment of cancer therapy, as well as for determining the recurrence after therapy of most cancers, including lung cancer, gastrointestinal cancer, breast cancer, and malignant lymphoma. PET/CT has become the new standard approach to imaging in the diagnosis and management of many cancer patients.

Present role and future prospects of positron emission tomography in clinical oncology

Positron emission tomography (PET) has emerged as a significant molecular imaging technique in clinical oncology and cancer research. PET with 18F‐fluorodeoxyglucose (18F‐FDG) demonstrates elevated glucose consumption by tumor cells, and is used clinically for the accurate staging and restaging of cancer, planning of radiotherapy, and predicting response or lack of response in the early stages of treatment. Combined PET and computed tomography (PET‐CT) provides both functional and morphological information of the disease to allow accurate diagnosis of cancer. PET with new radiotracers such as protein synthesis markers and proliferation markers, as well as hypoxia and receptor‐binding agents, will offer patient‐specific images in order to yield tailored diagnostic and prognostic information. (Cancer Sci 2006; 97: 1291–1297)

Current status of cancer therapy with radiolabeled monoclonal antibody

Molecular targeting therapy has become a relevant therapeutic strategy for cancer. There are several monoclonal antibodies used for the treatment of malignant tumors. Radioimmunoconjugate is composed of antibody and radionuclide showing a synergistic effect of radiation and immunemediated cellular toxicity and thereby enabling increased efficacy and minimizing toxicity. Radioimmunotherapy using131I- and90Y-labeled anti-CD20 monoclonal antibodies is now indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade or transformed non-Hodgkin’s lymphoma (NHL), including patients who are refractory to anti-CD20 monoclonal antibody (rituximab) therapy in the United States. It has been exhibiting favorable anti-tumor efficacy in patients with NHL as compared with rituximab. Myelosuppression is the main side effect associated with the radioimmunotherapy but is usually reversible, and nonhematologic adverse reactions are mild to moderate.Following the impressive results of therapy using radiolabeled monoclonal antibodies for NHL, radioimmunotherapy for solid tumors has been examined; however, the results were unfavorable and did warrant further clinical trials as a single agent. Future studies on radioimmunotherapy for solid tumors should focus on the new strategies of targeting such as locoregional administration for intraperitoneal dissemination, and combination therapy with chemotherapy or cytostatic therapy. Although radioimmunotherapy for NHL has shown excellent results comparable to aggressive chemotherapy without severe adverse effects, additional clinical trials should be performed to define the proper role of radioimmunoconjugates as a relevant strategy for cure of NHL.

Evaluation of radioiodinated 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine as a ligand for SPECT investigations of brain nicotinic acetylcholine receptors

Abstract5-Iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), an A-85380 analog iodinated at the 5-position of the pyridine ring, was evaluated as a radiopharmaceutical for investigating brain nicotinic acethylcholine receptors (nAChRs) by single photon emission computed tomography (SPECT). [123/125I]5IA was synthesized by the iododestannylation reaction under no-carrier-added conditions and purified by high-performance liquid chromatography (HPLC) with high radiochemical yield (50%), high radiochemical purity (>98%), and high specific radioactivity (>55 GBq/μmol). The binding affinity of 5IA for brain nAChRs was measured in terms of displacement of [3H]cytisine and [125I]5IA from binding sites in rat cortical membranes. The binding data revealed that the affinity of 5IA was the same as that of A-85380 and more than seven fold higher than that of (−)-nicotine, and that 5IA bound selectively to the α4β2 nAChR subtype. Biodistribution studies in rats indicated that the brain uptake of [125I]5IA was rapid and profound. Regional cerebral distribution studies in rats demonstrated that the accumulation of [125I]5IA was consistent with the density of high affinity nAChRs with highest uptake observed in the nAChR-rich thalamus, moderate uptake in the cortex and lowest uptake in the cerebellum. Administration of the nAChR agonists (−)-cytisine and (−)-nicotine reduced the uptake of [125I]5IA in all regions studied with most pronounced reduction in the thalamus, and resulted in similar levels of radioactivity throughout the brain. [125I]5IA binding sites were shown to be saturable with unlabeled 5IA. Behavioral studies in mice demonstrated that 5IA did not show signs of behavioral toxicity. Furthermore, SPECT studies with [123I]5IA in the common marmoset demonstrated appropriate brain uptake and regional localization for a high-affinity nAChR imaging radiopharmaceutical. These results suggested that [123I]5IA is a promising radiopharmaceutical for SPECT studies of central nAChRs in human subjects.

Development of Injectable O-15 Oxygen and Estimation of Rat OEF

Cerebral metabolic rate for oxygen (CMRO2) and cerebral oxygen extraction fraction (OEF) are some of the most fundamental parameters to characterize the pathophysiologic status of cerebral tissue. Although O-15-labeled gases inhalation method is performed in clinical studies, application of the inhalation method on small animals requires too many intensive procedures. On this basis, the development of a new method to measure CMRO2 and OEF in small animals is of interest. This study was aimed at developing a method to assess CMRO2 and OEF using intravenously injectable oxygen (injectable 15O–O2) for small animals such as rats. Injectable 15O–O2, 72 MBq/mL of radioactivity, was obtained after 15O–O2 gas circulation into the artificial lung. OEF after injection of injectable 15O–O2 was calculated using the same equation as that applied to the bolus inhalation of 15O–O2 gas method. Values of 44 ± 4.5 mL · min−1 · 100 g−1 of CBF and 0.54 ± 0.11 of OEF were obtained (n = 13). This OEF value was well accordance with OEF evaluated by arterial-venous difference of oxygen concentration (0.57 ± 0.13). This method is useful to study the CMRO2 and OEF in small animals using an animal positron emission tomography system. It may accelerate the basic research of several cerebral perfusion diseases.

Diagnosis of maxillofacial tumor withl-3-[18F]-fluoro-α-methyltyrosine (FMT) PET: a comparative study with FDG-PET

Objectives: To comparel-3-[18F]-fluoro-α-methyltyrosine (FMT)-positron emission tomography (PET) and 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-PET in the differential diagnosis of maxillofacial tumors.Methods: This study included 36 patients (16 males, 20 females; 31–90 years old) with untreated malignant tumors (34 squamous cell carcinoma, one mucoepidermoid carcinoma, one rhabdomyosarcoma) and seven patients (five males, two females; 32–81 years old) with benign lesions. In all patients, both FMT-PET and FDG-PET were performed within two weeks before biopsy or treatment of the lesions. To evaluate the diagnostic usefulness of FMT-PET and FDG-PET, visual interpretation and semiquantitative analysis were performed. PET images were rated according to the contrast of tumor uptake as compared with background, and were statistically analyzed. As a semiquantitative analysis, standardized uptake values (SUV) of the primary tumors were measured, and the SUV data were analyzed using receiver operating characteristic (ROC) curves.Results: The mean SUV of the malignant lesions were significantly higher than those of the benign lesions in both FMT-PET (2.62±1.58 vs. 1.20±0.30, p<0.01) and FDG-PET (9.17±5.06 vs. 3.14±1.34, p<0.01). A positive correlation (r=0.567, p<0.0001, n=46) was noted between FMT and FDG. ROC analysis revealed that there was no statistically significant difference in SUVs between FMT and FDG for differentiating malignant tumors. In 27 of 36 patients, FMT-PET had better contrast of malignant tumor visualization to the surrounding normal structures by visual assessment (p<0.005, binomial proportion test).Conclusions: Differential diagnosis of FMT-PET based on the uptake in maxillofacial tumors is equivalent to FDG-PET. However, the contrast of FMT uptake between maxillofacial tumors and the surrounding normal structures is higher than that of FDG, indicating the possibility of accurate diagnosis of maxillofacial tumors by FMT-PET.

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 Ringers 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.

5-[ 123I]iodo-A-85380: Assessment of pharmacological safety, radiation dosimetry and SPECT imaging of brain nicotinic receptors in healthy human subjects

Recently, 5-[123I]iodo-3-(2(S)-azetidinylmethoxy)pyridine ([123I]5IA) was developed as a ligand for imaging the nicotinic acetylcholine receptor (nAChR) in human brain using single photon emission computed tomography (SPECT). In the present study, the toxicity and radiation absorbed dose of [123I]5IA were investigated.Behavior and physiological parameters were examined in mice and rats after administration of 5IA. There were no changes in these parameters in animals administered 1 μg/kg of 5IA or less, indicating that the no observed effect level (NOEL) of 5IA was 1 μg/kg. [123I]5IA was then administered to healthy human subjects and serial whole-body images were acquired over 24 hr. Initially, high levels of radioactivity were observed in the liver and urinary bladder and moderate levels in the lungs, kidneys, and brain. Whole brain activity at 1 hr was 4.6 ± 0.4% of the injected dose and this value gradually decreased with time. The majority (~75%) of the radioactivity was excreted in urine within 24 hr, and less than 1% remained in all organs tested. The biological half-life of [123I]5IA averaged 7.2 ± 4.0 hr. Based on the biodistribution data, radiation absorbed doses were estimated using MIRDOSE 3.1 software with the dynamic bladder model and the ICRP gastrointestinal (GI) tract model. Consequently, the effective dose equivalent was estimated to be 30 ± 1.4 μSv/MBq, which is an acceptable radiation burden. Having determined the safety of this compound, we performed SPECT imaging in a healthy human subject using 171 MBq of [123I]5IA. SPECT images clearly revealed a cerebral distribution of radioactivity that was consistent with the known distribution of central nAChRs in humans. These results suggest that [123I]5IA is a promising ligand for imaging nAChRs in humans, with an acceptable dosimetry and pharmacological safety at the dose required for adequate SPECT imaging.

Regional alterations of myocardial norepinephrine transporter density in streptozotocin-induced diabetic rats: implications for heterogeneous cardiac accumulation of MIBG in diabetes

Abstract. Cardiac scintigraphic studies using iodine-123 labeled metaiodobenzylguanidine ([123I]MIBG) have previously demonstrated the heterogeneous myocardial accumulation of radioactivity in diabetes. In this study, we investigated the myocardial regional distribution of [125I]MIBG and the effects of regional myocardial blood flow, myocardial norepinephrine (NE) content, and norepinephrine transporter (NET) function on regional [125I]MIBG accumulation in streptozotocin-induced diabetic (STZ-D) rats. Dual-isotope autoradiographic studies using [125I]MIBG and technetium-99m labeled hexakis (2-methoxy-2-isobutylisonitrile) (99mTc-MIBI), a tracer for the measurement of myocardial blood flow, were carried out to investigate the changes in regional myocardial blood flow in STZ-D rats. Uptake of [125I]MIBG was similar between the anterior wall and the inferior wall in control rats. On the other hand, in STZ-D rats, uptake of [125I]MIBG in the inferior wall was significantly less than that in the anterior wall. Uptake of 99mTc-MIBI was not significantly different between the anterior and inferior walls in control or STZ-D rats, indicating that myocardial blood flow did not change regionally in either control or STZ-D rats, and that the blood flow was not responsible for the heterogeneity of the distribution of [125I]MIBG in STZ-D rats. In STZ-D rats, cardiac NE concentrations determined using an HPLC-electrochemical detection (ECD) system were significantly increased in both the anterior and the inferior wall, although there was no significant difference in NE concentration between the anterior and inferior walls in control or STZ-D rats. Furthermore, the density and affinity of NET were investigated by studying the binding of [3H]desipramine to cardiac membranes. The Bmax values of the NET in the anterior wall were not significantly different between control and STZ-D rats, but the Bmax value of the NET in the inferior wall was significantly lower in STZ-D rats than in controls. In conclusion, myocardial MIBG uptake was reduced in the inferior wall of STZ-D rats compared with control rats; this decrease was correlated with the decrease in NET density, but was not dependent on the regional myocardial blood flow and NE concentration. These results suggest that regional fluctuations in NET levels in the inferior wall contribute to heterogeneous MIBG accumulation in diabetes.