Synthesis of a <Superscript>188</Superscript>Re–DTPMP complex using carrier-free <Superscript>188</Superscript>Re and study of its stability

Labeling of diethylenetriamine-N,N,N′,N″,N″-pentakis(methylenephosphonic) acid (DTPMP) with rhenium-188 using stannous chloride as a reducing agent has been investigated. Dependence of the yield of the ¹⁸⁸Re–DTPMP complex on the concentration of the reducing agent, pH, reaction time, temperature, ascorbic acid and amount of carrier added has been studied. Under optimum conditions, the labeling yield of ¹⁸⁸Re–DTPMP complex is 95% for the carrier-free ¹⁸⁸Re but with the carrier-added ¹⁸⁸Re the labeling yield is more than 97%. Furthermore, the stability of the ¹⁸⁸Re–DTPMP complex against pH change and dilution with saline has been also studied. It is found that the addition of carrier stabilizes the ¹⁸⁸Re–DTPMP complex against pH change and dilution.     

188Rhenium-glucoheptonate: A radiopharmaceutical for intravascular radiation therapy

The preparation of ¹⁸⁸Re-glucoheptonate (GH) is described using ¹⁸⁸Re, which was obtained from an alumina based ¹⁸⁸W/¹⁸⁸Re generator. The dependence of the radiolabeling yields of ¹⁸⁸Re-GH on reducing agent concentration, GH concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of ¹⁸⁸Re-GH was ~99%. The ITLC technique was employed to monitor the different species formed. A biodistribution study of ¹⁸⁸Re-GH was carried out in rats and compared to the biological behavior of ^99mTc-GH.     

Separation of Clinical Grade 188Re from 188W Using Polymer Embedded Nanocrystalline Titania

Currently, ¹⁸⁸Re is obtained from ¹⁸⁸W/¹⁸⁸Re chromatographic generator containing alumina which has a limited capacity (~80 mg Wg^?1) for ¹⁸⁸W. This results in high bolus volumes of ¹⁸⁸Re, which often needs to be concentrated before radiolabeling. We have demonstrated the feasibility of using polymer embedded nano crystalline titania (TiP), a novel high capacity sorbent material (~300 mg Wg^?1), for developing a ¹⁸⁸W/¹⁸⁸Re chromatographic generator. A TiP based chromatographic ¹⁸⁸W/¹⁸⁸Re generator was developed in which ¹⁸⁸Re could be eluted with 0.9% saline solution. About 90% of the ¹⁸⁸Re could be recovered in the first 4–5 mL of total activity with more than 80% yield. The purity of ¹⁸⁸Re is adequate for clinical applications.     

Separation of Clinical Grade 188Re from 188W Using Polymer Embedded Nanocrystalline Titania

Currently, ¹⁸⁸Re is obtained from ¹⁸⁸W/¹⁸⁸Re chromatographic generator containing alumina which has a limited capacity (~80 mg Wg⁻¹) for ¹⁸⁸W. This results in high bolus volumes of ¹⁸⁸Re, which often needs to be concentrated before radiolabeling. We have demonstrated the feasibility of using polymer embedded nano crystalline titania (TiP), a novel high capacity sorbent material (~300 mg Wg⁻¹), for developing a ¹⁸⁸W/¹⁸⁸Re chromatographic generator. A TiP based chromatographic ¹⁸⁸W/¹⁸⁸Re generator was developed in which ¹⁸⁸Re could be eluted with 0.9% saline solution. About 90% of the ¹⁸⁸Re could be recovered in the first 4–5 mL of total activity with more than 80% yield. The purity of ¹⁸⁸Re is adequate for clinical applications.

     

Production of carrier-free 188Re in the past ten years in Taiwan

Twenty clinical scale alumina-based ¹⁸⁸W/¹⁸⁸Re generators and carrier-free ¹⁸⁸Re has been produced at the Institute of Nuclear Energy Research (INER-Taiwan) for over ten years. 2845.6 GBq (76.9 Ci) of ¹⁸⁸Re-perrhenate solution has been eluted from generators during the past ten years. We have used the harvesting ¹⁸⁸Re solution for labeling radiopharmaceuticals, such as ¹⁸⁸Re-HEDP, ¹⁸⁸Re-MDP, ¹⁸⁸Re-microsphere, ¹⁸⁸Re-lipiodol, and ¹⁸⁸Re-sulfur colloid, etc. The average eluting yield of ¹⁸⁸Re is 78.6±5.8% that was investigated at 1115 harvesting times from 20 generators. Each generator can be used more than six months but the Millipore needs to be changed every two months for smooth harvesting and high yield of ¹⁸⁸Re solution.     

Formulation of a freeze-dried kit for 188Re-MAG3 and its quality control

The synthesis of ¹⁸⁸Re-MAG₃ is described using ¹⁸⁸Re, which was obtained from the alumina based ¹⁸⁸W/¹⁸⁸Re generator. Dependence of the radiolabeling yields of ¹⁸⁸Re-MAG₃ on reducing agent concentration, Bz-MAG₃ concentration, pH, temperature and incubation time was examined. In the case of optimum conditions the yield of ¹⁸⁸Re-MAG₃ was 98%. TLC and HPLC techniques were employed to monitor the different species formed. Biodistribution study of ¹⁸⁸Re-MAG₃ was carried out in rats and compared with behavior of ^99mTc-MAG₃.     

An improved synthesis of S-benzoyl mercaptoacetyltriglycine as BFCA and the labeling of IgG with carrier-free 188Re

S-benzoyl mercaptoacetyltriglycine (S-Bz-MAG₃) was synthesized and labeled with carrier-free ¹⁸⁸Re. The overall yield of S-Bz-MAG₃ is higher than those published in the literature. Dependence of the labeling yield of ¹⁸⁸Re-MAG₃ upon concentration of reducing agent, pH, reaction time, and other parameters was examined and optimum conditions were obtained. The labeling yield of ¹⁸⁸Re-MAG₃ was more than 98%. The concentration procedure was succeeded with Sep-Pak C18 column to obtain highly concentrated ¹⁸⁸Re-MAG₃. The experimental conditions of labeling of IgG with carrier free ¹⁸⁸Re via S-Bz-MAG₃ as a bifunctional chelating agent (BFCA) by pre-radiolabeling of the chelate was studied. The conjugation conditions were optimized. The stability of ¹⁸⁸Re-MAG₃-IgG in vitro was high. The results of this studiy may be useful for ¹⁸⁸Re labeling of MAbs for radioimmunotherapy.     

An improved tungsten-188/rhenium-188 gel generator based on zirconium tungstate

An improved¹⁸⁸W-¹⁸⁸Re gel generator based on Zr tungstate is described. The influence of synthesis parameters and pre-treatment conditions on¹⁸⁸Re elution yields and the¹⁸⁸W breakthrough was studied with 0.15M aqueous solution of NaCl at pH 5.3 to 7.3 as well as with some organic solvents. An elution efficiency of 80% was achieved during 3 month of explotation with 0.15M NaCl at pH=6.3. The¹⁸⁸W breakthrough was 10^–4 to 10^–3%. The¹⁸⁸W breakthrough may be decreased to 10^–6% when converted into tandem generator with an alumina column. However,¹⁸⁸Re yields are reduced by 8–12% with a tandem generator.     

Comparison of the efficacy of 177Lu-EDTMP, 177Lu-DOTMP and 188Re-HEDP towards bone osteosarcoma: an in vitro study

Among the radiopharmaceuticals harnessed for palliation of bone pain in osseous metastases patients, ¹⁷⁷Lu labeled phosphonates such as EDTMP (Ethylene diamine tetramethylene phosphonic acid) as well as DOTMP (1,4,7,10-tetraaza-cyclo-dodecane-1,4,7,10 tetraethylene phosphonic acid) and ¹⁸⁸Re-labeled HEDP (1,1-hydroxyethylene diphosphonic acid) seem to be the most favorable for treatment of small and medium/large size bone lesions, respectively. A comparative assessment of ¹⁷⁷Lu-EDTMP, ¹⁷⁷Lu-DOTMP and ¹⁸⁸Re-HEDP in osteosarcoma tumor cell line was carried out to evaluate their relative efficacy. It was found that ¹⁸⁸Re-HEDP is more potent in induction of cell toxicity and apoptosis compared to the ¹⁷⁷Lu-EDTMP and ¹⁷⁷Lu-DOTMP, thus ¹⁸⁸Re-HEDP might have great clinical significance.

     

2,5-Diamino-5,5-diphosphonovaleric Acid as a Ligand for an Osteotropic <Superscript>188</Superscript>Re Radiopharmaceutical

A modified method for the preparation of 2,5-diamino-5,5-diphosphonovaleric acid (DADP5) has been developed in the search for new synthetically available organic ligands to produce ¹⁸⁸Re radiopharmaceuticals with an increased accumulation in the bone tissue. Interaction of the obtained acid with ¹⁸⁸Re was studied by radio-TLC. An optimal system for separating unbound ¹⁸⁸Re and labeled complex in a yield of at least 95% was found. The biological distribution of ¹⁸⁸Re-DADP5 was studied based on direct radiometric data. The osteotropicity of ¹⁸⁸Re-DADP5 and its increased accumulation in bone fracture sites, which represent oncological pathology models, was detected at a level comparable to known radiopharmaceuticals.     

188W-188Re gel generators based on metal tungstates

Gel generators based on Zn, Co, Ni, Mn and Pb tungstates were prepared as potential supports for the development of¹⁸⁸Re radiopharmaceuticals. Factors which affected either the elution efficiency of¹⁸⁸Re or the breakthrough of¹⁸⁸W were examined.¹⁸⁸Re was produced as perrenate when the generators were eluted with saline (0.15M NaCl) and different organic solvents. The elution yield of¹⁸⁸Re decreased for the various gel supports as: Zn (75%), Co (60%), Ni (37%), Mn (24%), Pb (15%). When a tandem system comprised of a chromatographic alumina column was utilized in combination with the gel generator the¹⁸⁸W breakthrough was controlled to of the order of 10^–6%.     

Radiosynthesis and evaluation of 188Re-c(RGDyK)-His as a novel radiotherapeutic agent for integrin αvβ3 targeting tumour

The successes of noninvasive methods to visualize and quantify integrin α_vβ₃ expression in vivo have paved the way for radiolabeling anti-integrin therapy in clinic. Arginine-glycine-aspartice (RGD) peptide and related derivatives labeled with radionuclides for radio-therapy, which specifically targeting integrin α_vβ₃-positive tumors, could be used to treat these tumors. We have labeled c(RGDyK)-His, a RGD derivative, with ¹⁸⁸Re and the radio-therapy efficiency has been evaluated in model nude mice. c(RGDyK)-His was labeled with ¹⁸⁸Re by chelating with [¹⁸⁸Re(CO)₃(H₂O)₃]⁺ under a slightly basic condition. The in vitro specific binding affinity to U87 MG cell lines and the biodistribution of ¹⁸⁸Re-c(RGDyK)-His in the animal tumor models was measured. The inhibitory effects of ¹⁸⁸Re-c(RGDyK)-His were observed more than 1 month, and evaluated by microPET/CT imaging with ¹⁸F-FDG. Results of in vivo, cell uptake demonstrated ¹⁸⁸Re-c(RGDyK)-His had a high specific binding affinity to receptor integrin α_vβ₃. In biodistribution experiment, ¹⁸⁸Re-c(RGDyK)-His was accumulated in the tumor and cleared fast from the normal tissues. In radiotherapy study, tumor growth inhibition was significantly higher in the treatment groups than in the control groups. These studies showed that ¹⁸⁸Re-c(RGDyK)-His could be effectively used for integrin α_vβ₃ targeting therapy. This may offer a potential therapeutic strategy for the treatment of integrin-positive tumors in clinic.     

Production of carrier free <Superscript>188</Superscript>Re radioisotope generator based on aluminum tungstate matrix

Improved radionuclide generator include a substantially insoluble salt of a radioactive parent which may be directly packed in column for subsequent elution of the daughter radionuclide. An improved ¹⁸⁸Re generator was prepared by reacting a radioactive tungsten (¹⁸⁸W) as parent radionuclide incorporated with aluminum chloride to obtain an insoluble radioactive aluminum tungstate matrix. The investigated matrix was characterized on the basis of the chemical composition, IR, thermal analysis and mechanical stabilities. The factors affecting the elution performance were studied such as influence of pH, molar ratio and drying temperature. From the obtained data, the molar ratio W:Al was 1.5:1 at pH = 4, the matrix dried at 105 °C for 2 h. Chromatographic and multichannel analysis has been currently used to investigate the radiochemical and radionuclidic purity respectively on eluted ¹⁸⁸Re. An elution yield more than 80%, with radiochemical purity <98% and radionuclidic purity <99% with a ¹⁸⁸W break through >10⁻⁴% of the column. The Al⁺³ and W contents value were about 2 and 3 μg/mL eluate. The obtained data approved the stability of the prepared generator and its suitability for medical application.     

Reactor production and processing of therapeutic radioisotopes for applications in nuclear medicine

In this paper the reactor production of a variety of therapeutic radionuclides of current clinical interest are discussed. Examples include radioisotopes produced by single neutron capture and those which are available from –/decay of reactor-produced parent radioisotopes. Two examples of generator parents produced by double neutron capture of targets are also discussed. One key example in this category is¹⁸⁸W, produced from irradiation of enriched¹⁸⁶W. The production of¹⁸⁸W in the ORNL High Flux Isotope Reactor and the fabrication and performance of the first production level large-scale clinical prototype¹⁸⁸W/¹⁸⁸Re generators are also described.     

186Re/188Re labeled polypeptide microspheres as a potential radiation synovectomy agent

Polypeptide microspheres containing polycysteine crosslinked with polylysine were prepared and radiolabeled with¹⁸⁶Re and¹⁸⁸Re. High labeling yields with the microspheres with both¹⁸⁶Re and¹⁸⁸Re (97%) were obtained, and above 99% retention of radiolabels in water in 24 hours was obtained. Rhenum-186 labeled polycysteine and polylysine microspheres (11 ratio, 20 m as mean diameter) were injected intra-articularly into the rear stifes (knee joints) of normal New Zealand white rabbits. About 87% of injected dose was retained in rabbit stifles and adjacent tissues in 96 hours after injection, while most of the activity lost from the joints was excreted in the urine. Due to its simplicity of preparation and radiolabeling, versatility, and biodegradability, this type of conjugate system may become the therapeutics of choice for radiation synovectomy.     

Analytical and radioanalytical quality control of purity and stability of radiopharmaceutical compound [186gRe]Re-HEDP for bone metastases pain palliation

Summary The nuclear properties of ^186gRe make it a useful agent for radionuclide therapy and imaging. The coordination compound [^186gRe]Re-HEDP has proved to be a successful bone seeking agent for palliation of metastatic bone pain. Chemical, radiochemical and radionuclidic purity of commercial radiopharmaceutical [^186gRe]Re-HEDP have been checked by means by γ- and β-spectrometries, INAA and paper radio-chromatography. The results indicate a good radionuclidic purity, with levels of contamination from the short-lived ¹⁸⁸Re well below the required specifications. After injection of the radiopharmaceutical, the radiochemical measurements conducted in vivo, on biological matrices, blood, plasma and urine, have shown that, entering the systemic circulation, ^186gRe dissociates from the bis-phosphonate complex as hydrosoluble [^186gRe]ReO₄-, and the two chemical species follow different biokinetics.     

Strategic Evaluation of the Traceless Staudinger Ligation for Radiolabeling with the Tricarbonyl Core

The traceless Staudinger ligation with its two variants is a powerful biorthogonal conjugation method not only for the connection of biomolecules, but also for the introduction of fluorescence- or radiolabels under mild reaction conditions. Herein, the strategic evaluation of the traceless Staudinger ligation for radiolabeling ^99mTc using the fac-[Tc(CO)₃]⁺ core is presented. A convenient and high-yielding three-step synthetic procedure of dipicolylamine-based phosphanols as ligands for the mild radiolabeling was developed. The labeling was accomplished using a tricarbonyl kit and a ^99mTc-pertechnetate generator eluate showing 87% radiochemical conversion. The respective rhenium-based, non-radioactive reference compounds were synthesized using (Et₄N)₂[Re(CO)₃Br₃] as precursor. All products were analyzed by NMR, MS, and elemental analysis. Additional XRD analyses were performed.     

Separation of lithium isotope by NTOE compound

In recent years chances of using rhenium-186 and rhenium-188 as radioactive isotopes in diagnostic and therapeutic applications are increased very much due to the characteristic radiochemical and chemical properties of these two radioisotopes. In particular, chemical similarities between⁹⁹Tc and^99mTc pair and¹⁸⁶Re and¹⁸⁸Re pair make it easier to correlate the two groups of compounds. Rhenium-188 is generated from the beta-decay of tungsten-188 which was produced by double neutron capture on enriched tungsten-186 oxide. It is of great interest to examine the impurities in the eluate by radiochemical neutron activation. For this purpose, the preconcentration of the impurities in samples were necessary, and it was achieved by adsorption on hydrated magnesium oxide.     

Pyridyl derivatives provide new pathways for labeling protein with fac-[<Superscript>188</Superscript>Re(CO)<Subscript>3</Subscript>(H<Subscript>2</Subscript>O)<Subscript>3</Subscript>]<Superscript>+</Superscript>

The purpose of this work was to indirect label IgG with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺ and to check the radiochemical behavior of the labeled product. The compound of (bis(2-pyridylmethyl)-amino)-acetic acid (L²H) was synthesized and labeled with fac-[¹⁸⁸Re(CO)₃(H₂O)₃]⁺. The labeling yield of ¹⁸⁸Re(CO)₃–L²H was more than 90%. The effects of protein concentration, reaction time, pH and reaction temperature of labeling of IgG with ¹⁸⁸Re(CO)₃–L²H were investigated. The conjugation conditions were optimized. The labeled product was analyzed by size exclusion HPLC and TLC. The stability of ¹⁸⁸Re(CO)₃–L²H–IgG in vitro was high. The results of this study may be useful for [¹⁸⁸Re(CO)₃(H₂O)₃]⁺ labeling of protein for radioimmunotherapy.     

Separation of yttrium from strontium in the aqueous phase of the water/nitrobenzene extraction system

A rapid separation for carrier-free ⁹⁰Y in the aqueous phase of the water/nitrobenzene extraction system from an ⁹⁰Y/⁹⁰Sr generator was proposed. After two-stage extraction separation, chemical yield of ⁹⁰Y in the final aqueous phase was roughly 80%, while ⁹⁰Sr radionuclide impurity in this phase containing carrier-free ⁹⁰Y was 10^-6%.