P.R Unni

177Lu-labeled cyclic polyaminophosphonates as potential agents for bone pain palliation.

177Lu (T 1/2 = 6.71 d, Ebeta(max) = 497 keV) has radionuclidic properties suitable for use in palliative therapy of bone pain due to metastasis. 177Lu was produced in high-specific activity (3-4TBq/g) and excellent radionuclidic purity (100%) by thermal neutron bombardment of natural Lu target. Two cyclic tetraaminomethylene phosphonate ligands, namely DOTMP and CTMP were synthesized and radiolabeled with 177Lu. The 177Lu-DOTMP complex was formed with very high yield (> 99%) and showed excellent stability (up to 40 d at room temperature). Biodistribution of 177Lu-DOTMP was carried out in Wistar rats and the complex showed significant bone uptake (4.23%/g in femur and 5.23% in tibia at 3 h p. i.), rapid clearance from blood (no activity at 3 h p. i.) and minimum uptake in soft tissues.

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.

Preparation, stability studies and pharmacological behavior of [186Re]Re-HEDP.

99mTc-HEDP is widely used as a bone imaging agent and its Re analog [186Re]Re-HEDP is now well established as a therapeutic radiopharmaceutical for palliation of pain due to bone metastases. In the present paper, we report the work carried out for the preparation of stable 186Re-HEDP which retains RC purity up to 5 days when stored at 4 degrees C. 186Re was prepared by irradiation of natural Re metal at a flux of 3 x 10(13) neutrons/cm2/s for seven days and processed after a cooling period of four days. The specific activity of 186Re formed was approximately 35 mCi/mg. A complex with RC purity > 98% could be prepared by varying the reaction conditions. By carefully optimizing the reaction and storage conditions, a complex which was stable for over 4 days could be synthesized. Bio-distribution studies carried out in rats revealed approximately 30% bone uptake of 186Re-HEDP at 3 h postinjection which remained almost constant for 48 h, at which time there was negligible activity in other organs.

Tc-99m and Re-186 complexes of tetraphosphonate ligands and their biodistribution pattern in animal models

The syntheses of four alpha-aminomethyl phosphonates and their complexation studies with (99m)Tc and (186/188)Re are reported. Complexation conditions were standardized to give maximum yields, which ranged from 90-97%. The yields of complexation were estimated by paper chromatography. The (99m)Tc complexes were stable for more than 4 h, while the (186/188)Re complexes were stable for 3-8 days when stored at 4 degrees C. Biodistribution of these complexes in Wistar rats were carried out, and the uptake in bone and other soft tissue are detailed. Bone uptake of the (99m)Tc complexes varied from 40-60% at 30 min postinjection depending on the ligands. The uptake in soft tissue was minimum with all the complexes. A comparison of the biodistribution studies of the (99m)Tc complexes with that of the well-established radiopharmaceutical (99m)Tc-MDP was carried out for the purpose of evaluating the efficacy of the radiopharmaceutical preparation with the complexes of these ligands. The bone uptake of the (186/188)Re complexes varied from 19-28% corresponding to 1.6-3% per g at 3 h postinjection. The residual activity in both (99m)Tc and (186/188)Re complexes showed renal clearance.

[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.

Preparation of [186Re]Re-DMSA and its bio-distribution studies.

99mTc(V)-DMSA is widely used for imaging medullary carcinoma and hence 186/188Re(V)-DMSA is suggested as a potential agent for treating medullary carcinoma. In the present paper, we report the work carried out for the preparation of [186Re]Re(V)-DMSA and its bio-distribution studies in Wistar rats. The complex was prepared by reducing 186Re (100 micrograms, 0.54 microM, approximately 150 MBq) in the presence of DMSA (2 mg, 11 microM) with stannous chloride (0.4 mg, 2.2 microM) in acidic medium at pH 2. The reaction was taken to completion by heating the complex in a boiling water bath for 30 min. Bio-distribution studies carried out revealed that pharmacological behaviour of 186Re(V)-DMSA is similar to that of 99mTc(V)-DMSA except that the kidney uptake is marginally higher. The kidney uptake reduced significantly when the pH of the complex was adjusted to 8 prior to injection. The in vitro stability studies of this complex suggest that the product formed is stable and could be used for clinical trials.

Feasibility study for production of 175Yb: a promising therapeutic radionuclide.

Owing to its favourable decay characteristics 175Yb (T1/2 = 4.2 d, E beta(max) = 480 keV) can be regarded as a potential radionuclide for therapeutic applications. Production of 175Yb using (174Yb(n, gamma)175Yb) reaction by thermal neutron bombardment on natural ytterbium target is described. The activity of 175Yb produced as well as its radionuclidic purity under different irradiation conditions were determined by gamma-ray spectrometry using an HPGe 4 K MCA system and compared with theoretically calculated values. The radiochemical purity after chemical processing was determined by paper chromatography as well as paper electrophoresis techniques. It is found that 31 Ci/g (1145 GBq/g) of 175Yb can be produced with > 95% radionuclidic purity (with approximately 3% of 169Yb and approximately 2% of 177Lu) by irradiating natural Yb2O3 target at a thermal neutron flux of 3 x 10(13) n/cm2/s for a period of 5 d.

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.

186Re-1,4,8,11-tetraaza cyclotetradecyl-1,4,8,11-tetramethylene phosphonic acid : a novel agent for possible use in metastatic bone-pain palliation

In connection with our work on the development of 186Re-tetra-phosphonates with optimum properties for use in bone pain palliation, a novel cyclic tetraphosphonate derivative, has been synthesized, complexed with 186Re and evaluated with promising results. The ligand, which consists of a cyclic array of tetra-aminomethylphosphonate groups, was synthesized using orthophosphorus acid, 1,4,8,11-tetraazacyclotetradecane and formaldehyde. The labeling conditions with 186Re have been standardized under varying reaction conditions to give maximum yield. In a reaction volume of 1 mL, maximum complexation yield of 98% was observed at pH 2 using 0.1 mg Re (37-370 MBq) for a ligand concentration at 9 x 10(-2) M/L, under heating at 100 degrees C for 30 min with 2 mg of stannous chloride. The complex was found to be stable for 6 days with RC purity remaining approximately 97%. The complex was characterized by paper chromatography in saline and acetone, wherein the R(f) exhibited were 0.9 and 0, respectively. Biodistribution studies of the complex were performed in male Wistar rats. Activity in femur which was observed to be 1.8%/g (equivalent to about 23% of the injected activity in skeleton) at 3 h post injection remained almost constant up to 48 h. Minimum activity was observed in blood and other soft tissues. The complex showed major renal clearance. Scintigraphic images in rabbits after injecting 70-100 MBq of 186Re-CTMP and using a dual head gamma camera were observed to be superior to 186Re-HEDP, prepared by a procedure standardized by us. Insignificant activity was observed in other vital organs. The results suggest the suitability of the complex for further evaluation in higher animals for bone pain palliation.