N. Ramamoorthy

Production logistics of 177Lu for radionuclide therapy.

Owing to its favourable decay characteristics 177Lu [T(1/2)=6.71 d, Ebeta(max)=497 keV] is an attractive radionuclide for various therapeutic applications. Production of 177Lu using [176Lu (n,gamma)177Lu] reaction by thermal neutron bombardment on natural as well as enriched lutetium oxide target is described. In all, approximately 4 TBq/g (108 Ci/g) of 177Lu was obtained using natural Lu target after 7 d irradiation at 3 x 10(13) n/cm2/s thermal neutron flux while it was approximately 110 TBq/g (3000 Ci/g) of 177Lu when 60.6% enriched 176Lu target was used. In both the cases, radionuclidic purity was approximately 100%, only insignificant quantity of 177mLu [T(1/2)=160.5 d, Ebeta(max)=200 keV] could be detected as the radionuclidic impurity. Production logistics using different routes of production is compared. Possible therapeutic applications of 177Lu are discussed and its merits highlighted by comparison with other therapeutic radionuclides.

177Lu labelled polyaminophosphonates as potential agents for bone pain palliation

Polyphosphonate ligands labelled with radioisotopes decaying by moderate energy beta emission have shown utility as palliative agents for painful bone metastasis. 177Lu (T½ = 6.71 d, Eβmax = 497 keV) has radionuclidic properties suitable for use in palliative therapy of bone metastasis. 177Lu was produced at a high specific activity and excellent radionuclidic purity by thermal neutron bombardment of a target prepared from natural Lu. Three polyaminomethylene phosphonate ligands, abbreviated as EDTMP, DTPMP and TTHMP, were synthesized and radiolabelled with 177Lu. Complexation parameters were optimized to achieve maximum yields (97-99.5%). All the complexes were found to retain their stability at room temperature even 14 days after preparation. Biodistribution studies of the complexes were carried out in Wistar rats. All the complexes showed significant bone uptake (6-6.5%/g in tibia at 3 h post-injection (p.i.)) with rapid clearance from blood and minimum uptake in soft tissues. These studies reveal that 177Lu complexes with the synthesized ligands have a potential use in palliative treatment of painful bone metastasis.

Preparation and bioevaluation of 166Ho labelled hydroxyapatite (HA) particles for radiosynovectomy

The preparation of 166Ho labeled hydroxy apatite (HA) particles for radiosynovectomy applications is described in this paper. 166Ho was prepared by the irradiation of Ho2O3 at a flux of 1.8 x 10(13) neutrons/cm2/s for about 7 days. The irradiation resulted in the production of approximately 17 GBq of 166Ho activity at the end of six hours post end of bombardment and the corresponding specific activity was approximately 3-4 GBq/mg of Ho. The irradiated target was dissolved in 0.1 N HCl solution. Radionuclidic purity was ascertained by high resolution gamma ray spectrometry. HA particles were synthesized and characterized by X-ray diffractometry. Labeling studies were carried out with and without citric acid as a transchelating agent. Radiochemical yield and purity of the 166Ho-HA particles were ascertained by paper chromatography and by paper electrophoresis techniques. Labeling yield of >98% could be achieved at pH 7, with 40 mg of HA particles and 8.6 microg of Ho. 166Ho-HA particles prepared were stable for 72 h. Bio-evaluation of the 166Ho -HA particles were carried out by injecting approximately 74 MBq dose in 200 microL (approximately 8 mg of 166Ho-HA particles) directly into the arthritis induced knee joints as well as into the healthy knee joints of white New Zealand rabbits. Images of the injected joints of the animals recorded using a gamma camera at regular intervals showed good retention. Blood samples were collected from the animals and activity assayed in a scintillation detector. Experiments were also carried out under identical conditions in normal rabbits. In both the cases, it was observed that there was no significant extra articular leakage of the injected activity over the study period of 96 h post injection.

[186/188Re] rhenium-ethylene dicysteine (Re-Ec): preparation and evaluation for possible use in endovascular brachytherapy

188ReO(4)(-), (188)Re-MAG(3), and (188)Re-DTPA are currently under investigation as radiation sources in liquid-filled balloons for prevention of restenosis following coronary angioplasty. Because (99m)Tc-labeled ethylene dicysteine (EC) is a well-established agent for renal tubular function imaging, the use of [(188)Re] rhenium-labeled EC as a potential agent for prevention of restenosis after angioplasty is worth evaluation. In this article, the preparation and pharmacological behavior of [(188/186)Re]Re complex of EC are reported. The yield of the Re complex was optimized by varying the parameters of complexation. The complex prepared under the optimized conditions was found to be stable over a period of 7 days when stored at pH 2 and at 4 degrees C. The pharmacological behavior of [(188/186)Re]Re-EC confirms its similarity to (188)Re-MAG(3) and its superiority over (188)ReO(4)(-) for use in endovascular brachytherapy.

Production logistics and radionuclidic purity aspects of 153Sm for radionuclide therapy.

153Sm, an attractive therapeutic radionuclide, was produced by neutron activation of both natural Sm2O3 and 98% enriched 152Sm2O3 targets. The production logistics and radionuclidic purity aspects of 153Sm obtained using both these targets are discussed with respect to the intended end use for metastatic bone pain palliation (MBPP) in terminal cancer patients and radiation synovectomy (RS) of medium size joints. The specific activity of 153Sm obtained was around 11 GBq·mg−1 (approximately 300 mCi·mg−1) and 44 GBq·mg−1 (approx. 1200 mCi·mg−1) from natural and enriched targets, respectively. The level of the long-lived radionuclidic impurity burden in 153Sm obtained from the natural Sm2O3 targets, namely, due to 154Eu (5 Bq·MBq−1 153Sm (5 nCi·mCi−1 153Sm)) and 155Eu (75 Bq·MBq−1 153Sm (75 nCi·mCi−1 153Sm)), appears low enough not to pose a problem, both in the palliative treatment of terminal cancer patients (at 1.85-2.22 GBq (50-60 mCi) dose) as well as in RS (at 74 MBq (2 mCi) dose). The 154Eu content in 153Sm from the enriched target was comparable, while, as expected, the level of 155Eu was nearly two orders of magnitude lower. There is a notable overall advantage of 153Sm over the use of 186Re, the other radionuclide of interest for the same purposes.

Potential 166Ho radiopharmaceuticals for intravascular radiation therapy (IVRT)-I : [166Ho] holmium labeled ethylene dicysteine

The use of beta(-) emitting radionuclides in the control of restenosis in post angioplasty patients is currently under intense investigation at many leading cardiovascular research centers. (32)P coated metallic stents, (192)Ir wire source and balloons filled with an appropriate radionuclide solution such as of (188)Re, attached to catheter are being studied. (166)Ho has comparable radionuclidic properties to that of (188)Re, can be more easily produced and hence is an attractive alternative to (188)Re. Ethylene dicysteine complex of (166)Ho was prepared and its pharmacological behavior studied. Optimum conditions for the preparation of complex with respect to the reaction time, ligand concentration, pH of the reaction mixture as well as reaction temperature were standardized. The stability of the labeled complex at room temperature as well as at 4 degrees C was determined. Biodistribution pattern of the injected complex in Wistar rats was estimated at 10 min, 30 min and 3 h post injection. This study indicated that >90% of the injected (166)Ho-EC complex was excreted in urine within 3 h post injection, with insignificant retention in any major organ. These studies reveal that (166)Ho-EC could be a viable substitute for (188)Re compounds in radioactive liquid-filled balloon IVRT.

Commentary: supplies of molybdenum-99--need for sustainable strategies and enhanced international cooperation.

The field of functional diagnostic imaging has been dominated by nuclear medicine procedures thanks to the excellent features of Tc – nuclear and chemical characteristics, as well as inexpensive and abundant availability [1–3]. The latter attribute – ‘ease of availability’ – has been in question as never before since the fall of 2007 because of serious disruptions in supplies of the precursor nuclide, molybdenum-99 (Mo), which has stretched until February 2009. The vulnerability of irradiation services from the five old research reactors (RR) used for Mo production, compounded by certain other (unrelated) incidents, has led to approximately 20–70% cancellations or delays in patient services depending on the week and location of nuclear medicine centre [4,5]. The issues to be addressed in seeking sustainable solutions will, however, need to go far beyond the reactors. It is true that the current problems are related mainly to the reliance on five old reactors for irradiation of enriched uranium-235 targets for the production of fission-based Mo, but there are other important issues that should not be overlooked. These include, inter alia, the complex and demanding technological issues in fission molybdenum production combined with the scale of operations for acceptable business/economic reasons, a multicomponent complex chain of supply logistics, conflicts of commercial interests among the limited number of current major producers some of them implicitly conveying discouraging signals to new entrants, and the important and inevitable concerns with regard to the continuing use of highly enriched uranium (HEU) targets for fission-based Mo production [6]. It is imperative to consider all the above aspects in evolving holistic and long-lasting approaches to ensure reliable and secure supplies of Mo for the immediate future and for longterm requirements. Recent events and calls for addressing issues The weekly requirement of Mo is reported to be approximately 450 000 GBq at the time of reference (generally 6 days after the end of reactor irradiation) – that is, over 12 000 Ci (6-day Ci) – with almost 50% for the US market alone. The five reactors currently used for irradiations are NRU (51 years), Chalk River, Canada; BR2 (47 years), Mol, Belgium; HFR (47 years), Petten, The Netherlands; Osiris (42 years), Saclay, France; and SAFARI-1 (43 years), Pelindaba, South Africa. There are only four large-scale processing facilities for fission-based Mo – MDS Nordion, Canada; IRE, Belgium; Covidien, The Netherlands; and NTP, South Africa. The reactors are also not dedicated to the production of Mo and other radioisotopes, but provide services to other users and for research. Domestic production in the US was stopped long ago. The reasons for this are not known with certainty, but it could be the result of the comparative consideration of the costs involved in domestic reactor operations and the production of Mo versus the purchase of the finished product from commercial sources in Canada and Europe.

Post-elution concentration of 99TcmO4- by a single anion exchanger column: II. Preparation and evaluation of jumbo alumina column chromatographic generator for 99Tcm.

We report on the preparation and evaluation of a large size (jumbo) alumina column (∼40 g, 90×20 mm) chromatographic generator and post-elution concentration of 99Tcm using a single column of a weak anion exchanger. The generator was eluted with ∼40 ml of a modified single salt buffer solution of 1 : 1 v/v 0.025 M or 0.05 M NH4OAc:0.7 M AcOH. This eluate was then passed through a small column of DEAE cellulose, a common weak anion exchanger, to trap 99TcmO4−, which was recovered by elution in 6 ml of normal saline. This amounts to a 5- to 7-fold increase in radioactive concentration (RAC) of 99Tcm, when compared to the RAC on direct elution with normal saline from the same jumbo alumina column generator. The overall yield of 99Tcm was in the range of 70-90%. 99Mo breakthrough was 10−3-10−4%, radiochemical purity was >98%, and chemical purity, in terms of Al and Mo content, <10 ppm each. The compatibility of pertechnetate obtained by this method for preparing 99Tcm labelled formulations such as Tc-MDP and 99Tcm-ethyl cysteinate dimer was found to be satisfactory. These promising results open up the feasibility of using (n,γ) 99Mo adsorbed on a large (40-60 g) alumina column as a relatively more user-friendly source of 99Tcm in comparison to methyl ethyl ketone extraction, and as a producer-friendly process in comparison to the zirconium molybdate gel method.

Post-elution concentration of 99mTcO4− by a single anion exchanger column: I: Feasibility of extending the useful life of column chromatographic 99mTc generator

99mTc eluate in 0.7/0.35 M acetic acid and in 1:1 v/v 0.7 M acetic acid: 0.025 M ammonium acetate (30-40 ml) was conveniently concentrated by passing through a small column of a readily available weak anion exchanger, DEAE cellulose, (200 mg, 6 x 8 mm) and subsequent elution with 3 ml normal saline, with greater than 90% recovery. The quality of pertechnetate thus obtained and its compatibility for preparing 99mTc compounds were satisfactory. This method was successfully applied to the alumina column chromatographic generator produced in-house and to a commercial 99Mo-99mTc generator after extensive clinical use. Potential for much higher concentration factors with compacted anion exchanger cartridges as well as applicability for 188W-188Re generator are discussed.

188Re-ethylene dicysteine: a novel agent for possible use in endovascular radiation therapy.

Several agents, such as 188ReO4−, 188Re-MAG3 and 188Re-DTPA are currently under investigation as radiation sources in liquid-filled balloons for prevention of restenosis following coronary angioplasty. Bearing in mind the risk factor associated with leakage of radioactivity in the event of balloon rupture, the criteria sought in selecting suitable agents for endovascular radiation therapy (EVRT) are rapid clearance and low dose to vital organs. Since 99Tcm labelled ethylene dicysteine (EC) is a well established agent for renal tubular function imaging, the use of 186Re-ethylene dicysteine as a potential agent for prevention of restenosis after angioplasty has been evaluated previously. Therefore, it was of interest to evaluate the applicability of the more potential isotope of rhenium, 188Re, a high energy β-emitter (Eβmax = 2.12 MeV) with a suitable T1/2 = 16.9 h, obtainable carrier-free from the 188W-188Re generator, as an attractive and alternative radionuclide for labelling with L,L-EC. In this paper, the preparation and pharmacological behaviour of the 188Re complex of ethylene dicysteine are reported. The complex can be prepared in high yields (99.5%) under optimized conditions of pH 2-3, at a ligand concentration of 15 mM, 50 μg (0.18 mM) carrier rhenium and using 2 mg·mL−1 stannous chloride. On storage at 4°C, the RC purity was more than 97% after 48 h when prepared under optimum conditions. Biodistribution studies in Wistar rats showed the desired characteristics of fast blood clearance and low retention of activity in the vital organs (<2% in intestine, <1% in stomach, <0.5% in liver) with a high renal excretion (90.65±0.6%) at 3 h post-injection. These results confirm the advantages of using the 188Re-EC complex compared with perrhenate and other rhenium radiopharmaceuticals currently being used in balloons for EVRT.