Kazuyuki Hashimoto

Production method of no-carrier-added186Re

No-Carrier-Added186Re was produced using the186W(p,n)186Re nuclear reaction with 13.6 MeV protons on thick targets of 99.79% isotopically enriched186WO3. The theoretical excitation functions for producing186Re, and possible radionuclidic impurities of182Re,183Re, and184Re were calculated using the ALICE code. Cross-sections of the186W(p,n)186Re reaction were measured up to 20 MeV using the stacked target method with thin foils of natural composition tungsten metal. The experimental and theoretical excitation functions were in good agreement. Targetry used at the TIARA cyclotron, and a radiochemical separation scheme for186Re are described.

RHENIUM COMPLEXES LABELED WITH 186,188RE FOR NUCLEAR MEDICINE

Complexes labeled with 186Re and 188Re have been developed for the radiotherapy treatment of diseases because of the desirable nuclear properties of these radioisotopes and because rhenium possesses chemical properties similar to those of technetium, a well-established diagnostic agent. Production of 186Re has been carried out by two methods: one using the 185Re(n,γ)186Re reaction in a nuclear reactor and the other using the 186W(p,n)186Re reaction. From the viewpoint of specific activity, the former is useful when a high flux nuclear reactor is available, but the latter is practicable when a cyclotron is at hand. 188Re has been produced from the double neutron capture reaction of 186W. A generator of 188W/188Re can be successfully prepared when a high flux nuclear reactor is available. The preparation of rhenium complexes (HEDP and MDP) for treating painful bone cancer has been investigated in order to determine the optimum conditions in chemical procedures. Other complexes (DTPA and DMSA) of rhenium have been synthesized for the radiolabeling antibodies. These are reviewed in this paper as well as further studies on antibody labeling using bifunctional ligands.

Production of no-carrier-added 177Lu via the 176Yb(n, &;#947;)177Yb &;#8594; 177Lu process

No-carrier-added 177Lu was produced by the 176Yb(n,γ)177Yb→177Lu process using enriched 176Yb2O3. The radiochemical separation of the nca 177Lu from the macroscopic ytterbium target was investigated by reversed-phase ion-pair HPLC. Effects of the concentrations of 2-hydroxyisobutyric acid and 1-octanesulfonate in the eluent, the amount of Yb2O3, the type and length of the C18 column on the separation efficiency were examined. Under optimum conditions, the nca 177Lu was obtained in radiochemically pure form from 5 mg of Yb2O3 with a separation yield of 84%.

Generation of radioisotopes with accelerator neutrons by deuterons

A new system proposed for the generation of radioisotopes with accelerator neutrons by deuterons (GRAND) is described by mainly discussing the production of 99Mo used for nuclear medicine diagnosis. A prototype facility of this system consists of a cyclotron to produce intense accelerator neutrons from the natC(\(d\),\(n\)) reaction with 40 MeV 2 mA deuteron beams, and a sublimation system to separate 99mTc from an irradiated 100MoO3 sample. About 8.1 TBq/week of 99Mo is produced by repeating irradiation on an enriched 100Mo sample (251 g) with accelerator neutrons for two days three times. It meets about 10% of the 99Mo demand in Japan. The characteristic feature of the system lies in its capability to reliably produce a wide variety of high-quality, carrier-free, carrier-added radioisotopes with a minimum level of radioactive waste without using uranium. The system is compact in size, and easy to operate; therefore it could be used worldwide to produce radioisotopes for medical, research, and industrial...

Synthesis of a 188Re-HEDP complex using carrier-free 188Re, and a study of its stability

The synthesis of an Re-HEDP complex using carrier-free 188Re from the 188W/188Re generator was investigated. Stannous chloride was used as the reducing agent for the reduction of rhenium and l-ascorbic acid was used as an antioxidant in the reaction medium. Dependence of the yield of the 188Re-HEDP on the concentration of the reducing agent, pH, reaction time, temperature, ionic strength and amount of carrier added was examined. Under optimum conditions, the labeling yields of 188Re-HEDP was more than 95% for the carrier-free as well as the carrier-added 188Re. Differences of reaction conditions between 188Re-HEDP and 188Re-MDP were clearly observed. Furthermore, the stability of the 188Re complex against pH change and dilution with saline was also studied. It was found that the formation conditions of 188Re-HEDP, such as addition of a carrier, the temperature and pH, influenced its stability.

Synthesis of 188Re-MDP complex using carrier-free 188Re

Abstract The synthesis of a rhenium-MDP labelled compound using carrier-free 188Re from the 188W/188Re generator was investigated. Stannous chloride was used as the reducing agent for the reduction of rhenium. Dependence of the yield of Re-MDP upon the concentration of reducing agent, reaction time, antioxidant, pH, temperature, ionic strength and adding the carrier was examined. Under optimum conditions, the yields of Re-MDP were 85–89% using carrier-free 188Re and 92–95% using carrier-added 188Re. Furthermore, the stability of Re-MDP at different pHs was studied.

Skeletal affinity of Tc(V)-DMS is bone cell mediated and pH dependent

In spite of recent advances in bone cellular and molecular biology, there is still a poor correlation between these parameters and data obtained from bone scintigraphy. Diphosphonate derivatives radiolabelled with technetium-99m (Tc-BPs) have long been recognised as bone-seeking agents with an affinity for areas of active mineralisation. However, during clinical trials with a pH-sensitive tumour agent, the pentavalent technetium complex of dimercaptosuccinic acid [Tc(V)-DMS] showed a noticeable osteotropic character only in bone pathologies (bone metastases, Paget’s diseases) and lacked accumulation in normal mature bone. To decipher the osteotropic character of Tc(V)-DMS, a study at the cellular level was considered necessary. Moreover, to learn more about the role of Tc bone agents, acid-base regulation by bone tissue or cells was studied. First, biological parameters in body fluid were measured under systemic acidosis, induced by glucose administration, in normal and Ehrlich ascites tumour (EAT)-bearing mice. Then, in vivo biodistribution studies using Tc(V)-DMS or a conventional Tc-BP agent were carried out. The effect of glucose-mediated acidification on the skeletal distribution of the Tc agents in the mice provided valuable hints regarding the differential mediation of bone cells in skeletal tissue affinity for the agents. Thereafter, in vitro studies on osteoblast and osteoclast cells were performed and the comparative affinity of Tc(V)-DMS and Tc-BP was screened under diverse acidification conditions. Moreover, studies were also carried out on acid-base parameters related to the cellular uptake mechanism. Very specific pH-sensitive Tc(V)-DMS accumulation only in the osteoclastic system was detected, and use of Tc(V)-DMS in the differential detection of osteoblastic and osteoclastic metastases is discussed.

Usefulness of competitive inhibitors of protein binding for improving the pharmacokinetics of 186Re-MAG3-conjugated bisphosphonate (186Re-MAG3-HBP), an agent for treatment of painful bone metastases

PurposeWe have developed a 186Re-mercaptoacetylglycylglycylglycine complex-conjugated bisphosphonate (186Re-MAG3-HBP) for the treatment of painful bone metastases. We assumed competitive inhibitors of protein binding to be useful for procuring a favorable biodistribution of 186Re-MAG3-HBP for the palliation of bone pain because it has been reported that the concurrent administration of 99mTc-MAG3 and drugs with high affinity for serum protein produced competitive displacement at specific binding sites and enhanced total clearance and tissue distribution.MethodsThe displacement effects of several protein-binding inhibitors on the protein binding of 186Re-MAG3-HBP were investigated. Biodistribution experiments were performed by intravenously administering 186Re-MAG3-HBP into rats with ceftriaxone as a competitive protein-binding inhibitor or saline.ResultsThe protein binding of 186Re-MAG3-HBP in rat serum, human serum, and a human serum albumin solution was significantly decreased by the addition of ceftriaxone, which has high affinity for binding site I on serum albumin. In the biodistribution experiments, pretreatment with ceftriaxone enhanced the clearance of the radioactivity of 186Re-MAG3-HBP in blood and nontarget tissues but had no effect on accumulation in bone.ConclusionsThe findings suggested that the use of protein-binding competitive inhibitors would be effective in improving the pharmacokinetics of radiopharmaceuticals with high affinity for serum protein.

Adsorption of Db and its homologues Nb and Ta, and the pseudo-homologue Pa on anion-exchange resin in HF solution

Abstract Anion-exchange chromatography of element 105, dubnium (Db), produced in the 248Cm( 19F, 5n) 262Db reaction is investigated together with the homologues Nb and Ta, and the pseudo-homologue Pa in 13.9 M hydrofluoric acid (HF) solution. The distribution coefficient (Kd) of Db on an anion-exchange resin is successfully determined by running cycles of 1702 chromatographic column separations. The result clearly indicates that the adsorption of Db on the resin is significantly different from that of the homologues and that the adsorption of anionic fluoro complexes of these elements decreases in the sequence of Ta≈ Nb>Db≥Pa.

In vivo recognition of cyclopentadienyltricarbonylrhenium (CpTR) derivatives

In vivo metabolism of [(188)Re]tricarbonyl(carboxycyclopentadienyl)rhenium ([(188)Re]CpTR-COOH) and its glycine conjugate ([(188)Re]CpTR-Gly) was investigated to estimate the applicability of cyclopentadienyltricarbonylrhenium (CpTR) compounds to (186/188)Re-labeling reagents for polypeptides and peptides. Both [(188)Re]CpTR derivatives were stable after incubation in a buffered-solution and in murine plasma at 37 degrees C for 6 h. Plasma protein binding was hardly observed with the two derivatives. However, different biodistribution and metabolic fates were observed with the two CpTR derivatives. While more lipophilic [(188)Re]CpTR-COOH was excreted by both hepatobiliary and urinary excretion, the majority of less lipophilic [(188)Re]CpTR-Gly was excreted by urinary excretion. In addition, while [(188)Re]CpTR-Gly was rapidly excreted into urine as its intact structure, [(188)Re]CpTR-COOH was metabolized to more hydrophilic compounds including its glycine conjugate, [(188)Re]CpTR-Gly. Renal excretion of [(188)Re]CpTR-Gly was significantly reduced in probenecid retreated mice. The present studies reinforced that CpTR core remained stable under biological environment. CpTR-COOH was partially recognized as an aromatic acid and was metabolized as such. However, glycine conjugation rendered CpTR-COOH hydrophilic enough to be excreted into urine without further metabolism. These findings suggested that radiolabeling reagents that liberate [(186/188)Re]CpTR-Gly from covalently conjugated (186/188)Re-labeled polypeptides and peptides by the action of renal brush border enzymes would be useful to reduce renal radioactivity levels.