Arnold L. Beets

Processing of reactor-produced 188W for fabrication of clinical scale alumina-based 188W/188Re generators

Abstract The traditional technique for processing of reactor-irradiated 186 W-enriched tungsten oxide (WO 3 ) targets involves formation of 188 W-sodium tungstate solutions by target dissolution in 0.1 M NaOH. Following long irradiations (> 21 days) in the ORNL High Flux Isotope Reactor (HFIR) the 186 WO 3 targets contain a NaOH-insoluble 188 W-labeled black solid (approx. 30–50% of total activity) which decreases the yield and specific activity of the processed 188 W (e.g. 5–6 mCi/mg 186 W for a 79-day irradiation). The black material is postulated to represent a “tungsten blue” insoluble polymeric form of tungsten oxide, which we have now found to dissolve in 0.1 M NaOH containing 5% sodium hypochlorite solution. Complete dissolution results in a significant increase in the yield and specific activity of sodium 188 W-tungstate. As an alternative approach, irradiated 186 W-enriched metal targets dissolve in sodium hydroxide solution by cautious addition of 188 W-tungstate solutions prepared from processing of such metal targets show no evidence of residual black insoluble material. Specific activity values for completely dissolved HFIR-irradiated 186 W targets have increased to 10 mCi/mg (43.5 days) and 12.9 mCi/mg (49.2 days). Large clinical scale (> 1 Ci) generators prepared from hypochlorite-processed 186 W oxide or peroxide-processed 186 W metal targets exhibit the expected 188 Re high yield and low 188 W breakthrough.

Reactor-produced radioisotopes from ORNL for bone pain palliation

The treatment of painful skeletal metastases is a common clinical problem, and the use of therapeutic radionuclides which localize at metastatic sites has been found to be an effective method for treatment of pain, especially for multiple sites for which the use of external beam irradiation is impractical. There are currently several metastatic-targeted agents radiolabeled with various therapeutic radionuclides which are in various stages of clinical investigation. Since neutron-rich radionuclides are produced in research reactors and often decay by emission of beta- particles, most radionuclides used for bone pain palliation are reactor-produced. Key examples of radionuclides produced by single neutron capture of enriched targets include rhenium-186 and samarium-153. In addition, generator systems are also of interest which provide therapeutic daughter radionuclides from the decay of reactor-produced parent radionuclides. One important example is rhenium-188, available from generators via decay of reactor-produced tungsten-188. Tin-117m is an example of a reactor-produced radionuclide which decays with the emission of low-energy conversion electrons rather than by beta- decay. Each of these agents and/or radionuclides has specific advantages and disadvantages, however, the ideal agent for bone pain palliation has not yet been identified. The goal of this paper is to briefly review the production and use of several reactor-produced radionuclides for bone pain palliation, and to discuss the role of the ORNL High Flux Isotope Reactor (HFIR) for the production of many of these radionuclides.

Endovascular beta irradiation for prevention of restenosis using solution radioisotopes: pharmacologic and dosimetric properties of rhenium-188 compounds.

PURPOSE Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy. MATERIALS AND METHODS Rhenium-188 was obtained as [188Re]-sodium perrhenate by saline elution of an alumina-based 188W/188Re generator system (>500 mCi). High specific volume solutions of the [188Re]-sodium perrhenate (>50 mCi/ml) were obtained by post-elution concentration of the generator bolus by passage through a tandem silver cation/anion column system. Rhenium-188-labeled benzoylthioacetyltriglycine (MAG3) was prepared by stannous ion reduction of [188Re]-perrhenate in the presence of the benzyl-MAG3 substrate, and was characterized as a single radioactive component. Rhenium-188-perrhenate and [188Re]-MAG3 were administered to separate groups of Fischer rats, which were sacrificed at various times and the tissue distribution of 88Re determined in the major organs. Excretory products were also collected daily from separate groups of rats for each agent over 7 days. The effects of perchlorate and iodide preblocking and postdisplacement of thyroid uptake of [188Re]-perrhenate were also evaluated. RESULTS Organ uptake values were modest for both agents [<0.25 % injected dose(ID)/gram of tissue at 6 h] for all organs evaluated except for the thyroid, with the intestines and intestinal contents showing the highest uptake values (0.72-1.97 %ID/gram). Whereas thyroid uptake of 188Re after injection of [188Re]-MAG3 was low (0.16 %ID/gram), uptake after injection of [188Re]-perrhenate was higher and could be blocked by pretreatment with perchlorate (intravenous [IV]) or displaced by perchlorate posttreatment. Also, oral or IV iodide pre- or postadministration could also significantly block or displace thyroid uptake of [188Re]-perrhenate. Both [188Re] agents were excreted primarily via the urinary bladder. The excretion half-life of [188Re]-perrhenate was about 7 h; in contrast, the [188Re]-MAG3 complex showed 50% excretion in less than 2 h. The large intestines received the most significant adsorbed dose, with values of 2.0 cGy/ mCi for [188Re]-perrhenate and 4.6 x 10(-3) cGy/mCi for [188Re]-MAG3. CONCLUSIONS Rhenium-188-MAG3 shows more rapid urinary bladder excretion in rats than perrhenate and both agents show low organ uptake. Thyroid uptake of free [188Re]-perrhenate can be blocked or displaced with oral perchlorate administration. For the projected use of [188Re]-MAG3 for balloon inflation required for irradiation of the arterial wall, calculated organ dose values are within acceptable limits in the unlikely event of low pressure balloon rupture. Rhenium-188-MAG3 in solution is thus a new candidate for balloon dilation providing uniform endovascular irradiation following PTCA for restenosis therapy.

Synthesis of a new bisphosphonic acid ligand (SEDP) and preparation of a 188Re-(Sn)SEDP bone seeking radiotracer

The new bisphosphonate ligand SEDP (2-sulfonato-1,1-ethylidene bisphosphonic acid) has been synthesized and characterized, including the determination of the protonation constants, and used to form (188)Re-(Sn)SEDP from Na(188)ReO4. The title compound (188)Re-(Sn)SEDP shows slightly greater bone uptake and less kidney uptake than (188)Re-(Sn)HEDP in rat biodistribution studies.

Ascorbic acid/saline eluant increases 188Re yields after “wet” storage of 188W/188Re generators

Abstract We have evaluated several factors in an attempt to minimize the reduced yields observed after “wet” storage of 188 W/ 188 Re generators, which include the dispersion of 188 W-tungstic acid in the alumina column bed by pre-mixing with silica gel, incorporation of cupric ion as an antioxidant in the adsorbent, and elution of the alumina columns with saline solution containing ascorbic acid. The results demonstrate that dispersion of the 188 W-tungstic acid in a silicaalumina bed and the use of cupric ion do not significantly increase 188 Re yields after weekend “wet” storage. In contrast, addition of ascorbic acid at concentrations as low as 0.01% in the saline eluant was found to be an effective method of maintaining good 188 Re yields after “wet” weekend storage, resulting in Monday elution yields greater than 70%. Use of low concentrations of ascorbic acid is thus an effective alternative to drying the generator columns before storage.

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 β−/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.

Evaluation of Z-(R,R)-IQNP for the potential imaging of m2 mAChR rich regions of the brain and heart.

Alterations in the function or density of the m2 muscarinic (mAChR) subtype have been postulated to play an important role in various dementias such as Alzheimers disease. The ability to image and quantify the m2 mAChR subtype is of importance for a better understanding of the m2 subtype function in various dementias. Z-(R)-1-Azabicyclo[2.2.2]oct-3-y (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z-(R,R)-IQNP) has demonstrated significant uptake in cerebral regions that contain a high concentration of m2 mAChR subtype in addition to heart tissue. The present study was undertaken to determine if the uptake of Z-(R,R)-IQNP in these regions is a receptor mediated process and to identify the radiospecies responsible for binding at the receptor site. A blocking study demonstrated cerebral and cardiac levels of activity were significantly reduced by pretreatment (2-3 mg/kg) of (R)-3-quinuclidinyl benzilate, dexetimide and scopolamine, established muscarinic antagonists. A direct comparison of the cerebral and cardiac uptake of [I-125]-Z-(R,R)-IQNP and [I-131]-E-(R,R)-IQNP (high uptake in ml, m4 rich mAChR cerebral regions) demonstrated Z-(R,R)-IQNP localized to a higher degree in cerebral and cardiac regions containing a high concentration of the m2 mAChR subtype as directly compared to E-(R,R)-IQNP. In addition, a study utilizing [I-123]-Z-(R,R)-IQNP, [I-131]-iododexetimide and [I-125]-R-3-quinuclidinyl S-4-iodobenzilate, Z-(R,R)-IQNP demonstrated significantly higher uptake and longer residence time in those regions which contain a high concentration of the m2 receptor subtype. Folch extraction of global brain and heart tissue at various times post injection of [I-125]-Z-(R,R)-IQNP demonstrated that approximately 80% of the activity was extracted in the lipid soluble fraction and identified as the parent ligand by TLC and HPLC analysis. These results demonstrate Z-(R,R)-IQNP has significant uptake, long residence time and high stability in cerebral and cardiac tissues containing high levels of the m2 mAChR subtype. These combined results strongly suggest that Z-(R,R)-IQNP is an attractive ligand for the in vivo imaging and evaluation of m2 rich cerebral and cardiac regions by SPECT.

Resolution, in vitro and in vivo evaluation of fluorine-18-labeled isomers of 1-azabicyclo[2.2.2]oct-3-ylα-(1-fluoropent-5-yl)α-hydroxy-α-phenylacetate (FQNPe) as new PET candidates for the imaging of muscarinic-cholinergic receptor

1-Azabicyclo[2.2.2]oct-3-yl-α-(1-fluoropent-5-yl)-α-hydroxy-α-phenylacetate (FQNPe, 2), an analogue of 1-azabicyclo[2.2.2]oct-3-yl α,α-(diphenyl)-α-hydroxyacetate (QNB), was resolved into its four stereoisomers. In vitro binding assays of the stereoisomers of 2 demonstrated that while the (S,S)-isomer did not have significant receptor binding, the other stereoisomers of 2 bound with high affinity to the various mAChR subtypes [K i , nM: m1, (R,R), 0.33; (R,S), 1.4; (S,R), 3.8; m2, (R,R), 0.1; (R,S), 4.2; (S,R), < 75% binding; m3, (R,R), 0.34; (R,S), 3.1; (S,R), 7.6]. The (R,R)- and (R,S)-stereoisomers of 2 were radiolabeled with fluorine-18 via a two step procedure in radiochemical yields of 12-21% (n=2) and 9% (decayed corrected to beginning of synthesis), respectively. In vivo biodistribution studies demonstrated significant uptake of [ 18 F]-(R,R)-2 in cerebral mAChR-rich regions of rat brains up to 3 h post injection. Low accumulation of fluorine-18 in the bone indicated that [ 18 F]-(R,R)-2 displayed significant in vivo stability. In contrast [ 18 F]-(R,S)-2 demonstrated rapid washout from all cerebral regions. Preinjection of (R)-QNB (3 mg/kg) 1 h prior to the injection of [ 18 F]-(R,R)-2 blocked the uptake of activity in cerebral regions by approximately 90% while the preinjection of haloperidol (3 mg/kg) 1 h prior to the injection of [ 18 F]-(R,R)-2 demonstrated no statistically significant effect on the binding of the radiotracer. An ex vivo metabolic study utilizing [ 18 F]-(R,R)-2 demonstrated that greater than 96% of the organic soluble radioactivity which localized in the brain and heart at 1 h post-injection migrated on TLC with the same mobility as the parent Although [ 18 F]-(R,R)-2 did not demonstrate a desired in vitro or in vivo mAChR subtype selectivity, these results suggest that the introduction of a fluoroalkyl group in various benzylic analogues of QNB is an attractive radiolabeling moiety for further evaluation in the design of selective PET mAChR imaging ligands

Stereoselective synthesis, in vitro, and initial in vivo evaluation of 1-methylpiperidin-4-yl α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate (IPIP): a novel radioiodinated molecular probe with high affinity for the muscarinic receptor

Abstract 1-Methylpiperidin-4-yl α-hydroxy-α-(1-iodo-1-propen-3-yl)-α-phenylacetate (IPIP, Fig. 1) Fig. 1QNB and various radiolabeled mAChR antagonists. was investigated as a potential radioiodinated molecular probe targeted to the muscarinic receptor complex. The IPIP stereoisomers were synthesized via a chiral intermediate in >95% enantiomeric excess. The R-isomers demonstrated a M 1 to M 2 subtype selectivity of approximately 3 to 1 and the S-isomers demonstrated non-subtype selective binding in vitro . IPIP was radiolabeled with iodide-125 with an average radiochemical yield of 74.4% (±14.8, n=5), specific activities >800 mCi/μmol, and radiochemical purities >97%. In vivo the Z-isomers demonstrated high uniform cerebral uptake suggesting non-subtype selective binding. In contrast, E-R-IPIP, after allowing a low uptake in M 2 rich areas to clear, demonstrated a retention of activity in M 1 and M 4 rich cerebral regions. In addition, the cerebral uptake of E-R-IPIP and Z-S-IPIP were inhibited by 70–90% via pretreatment with R-QNB, an established muscarinic antagonist. An ex vivo metabolism study demonstrated Z-S-IPIP was stable at the receptor site with an absence of radiolabeled metabolites.