Grace Samuel

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.

Mannosylated dextran derivatives labeled with fac-[M(CO)₃]+ (M = (99m)Tc, Re) for specific targeting of sentinel lymph node.

Despite being widely used in the clinical setting for sentinel lymph node detection (SLND), (99m)Tc-based colloids (e.g., (99m)Tc-human serum albumin colloids) present a set of properties that are far from ideal. Aiming to design novel compounds with improved biological properties, we describe herein the first class of fully characterized (99m)Tc(CO)₃-mannosylated dextran derivatives with adequate features for SLND. Dextran derivatives, containing the same number of pendant mannose units (13) and a variable number (n) of tridentate chelators (9, n = 1; 10, n = 4, 11, n= 12), have been synthesized and fully characterized. Radiolabeled polymers of the type fac-[(99m)Tc(CO)₃(k³-L)] (12, L = 9, 13, L = 10, 14, L = 11) have been obtained quantitatively in high radiochemical purity (≥ 98%) upon reaction of the dextran derivatives with fac-[(99m)Tc(CO)₃(H₂O)₃]+. The highly stable compounds 13 and 14 were identified by comparing their HPLC chromatograms with the ones obtained for the corresponding rhenium surrogates fac-[Re(CO)₃(k³-10)] (13a) and fac-[Re(CO)₃(k³-11)] (14a), which have been characterized both at the chemical (NMR and IR spectroscopy, and HPLC) and physical level (DLS, AFM and LDV). Compounds 13a and 14a present a positive zeta potential (+ 7.1 mV, pH 7.4) and a hydrodynamic diameter in the range 8.4-8.7 nm. Scintigraphic imaging and biodistribution studies in Wistar rats have shown good accumulation in the sentinel node at 60 min postinjection (6.71 ± 2.35%, 13; and 7.53 ± 0.69%, 14), with significant retention up to 180 min. A clear delineation of the sentinel lymph node without significant washout to other regions was observed in the scintigraphic images. The popliteal extraction of 94.47 ± 2.45% for 14 at 1 h postinjection, as compared to 61.81 ± 2.4% for 13, indicated that 14 is a very promising compound to be further explored as SLN imaging agent.

Complexation studies with 90Y from a novel 90Sr-90Y generator

Some features of a novel 90Sr-90Y generator which employs supported liquid membrane (SLM) to separate carrier-free 90Y from 90Sr present in the high level waste of the spent fuel of reactor are described. After ascertaining the purity of 90Y particularly with respect to 90Sr breakthrough, its complexation was studied with a few oxo/aza donor ligands, such as DTPA, EDTMP, DOTA, TETA and a cyclic phosphonate, CTMP. These studies were primarily carried out to adjudge the quality of the 90Y obtained from a novel 90Sr-90Y generator and ascertain its usability for labelling biomolecules such as antibodies and peptides. The DOTA complexes are most stable at 37 C in human serum; they appear to be ideal bifunctional chelating agent for use in radioimmunotherapy with 90Y.

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.

A novel [186/188Re]-labelled porphyrin for targeted radiotherapy

The concept of labelling a porphyrin, a tumour-avid agent, with a radionuclide to evaluate its potential as a therapeutic modality is reported. A novel water-soluble porphyrin, namely meso-tetrakis[3,4-bis(carboxymethyleneoxy)phenyl]porphyrin, with suitable dicarboxylic acid groups as aromatic substituents in the periphery, was synthesized and characterized. The labelling of this porphyrin with 186/188Re, a β− emitter, was optimized by varying the reaction conditions. The complexation yield was >98% as estimated by paper chromatography in acetone and in saline. The radiochemical purity was found to remain at >98% when stored at 4°C for 24 h. Biodistribution studies in Swiss mice bearing fibrosarcomas showed an uptake of ∼3.5% per gram of tumour at 30 min post-injection. This uptake in the tumour was retained until 24 h post-injection with major activity showing renal clearance; no significant activity was present in other organs of interest. The tumour/blood and tumour/muscle ratios were observed to be 38 and 5, respectively, at 24 h post-injection, thereby indicating a possible therapeutic potential for tumours.

Technetium-99m complexes of polydentate amine-pyrrole and amine-thiophene ligands.

Novel polydentate amine-pyrrole and amine-thiophene ligands were synthesized and characterized by 1H and 13C NMR spectroscopy. Radiochemical studies with 99mTc were carried out at 0.1-100 microM of technetium. Complexation yields were estimated from thin layer chromatography (TLC), paper electrophoresis, and solvent extraction studies. The 99mTc complexes formed were found to be neutral and lipophilic. Complexes with the corresponding imine-ligands were formed in lower yields. Biodistribution studies of the 99mTc complexes of these ligands showed no significant uptake in brain or heart, and the clearance was mainly through the hepatobiliary system.

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.

Evaluation of 90y phosphate particles as a possible radiation synoviorthesis agent

Background90Y is one of the radioisotopes used extensively for therapy due to its favourable nuclear characteristics. Particles and colloids incorporating 90Y are being used for radiation synovectomy, especially in European countries. MethodsIn our present work, 90Y phosphate particles were prepared and evaluated for use in radiation synovectomy. The radioactive particles were prepared by reacting carrier added 90YCl3 with phosphoric acid. ResultsThe radiolabelling yield obtained was >95%. The particles were found to be stable in saline for up to 7 days of study at 37°C. Particle size analysis of inactive yttrium phosphate showed that most of the particles were in the size range of 2–20 μm. Biodistribution studies carried out by intra-articular injection of the particles into the knee joints of rats showed that ∼99% of the particles were retained in the joints with negligible radioactivity in the major organs even at 48 h post-injection. Scintigraphic studies in rabbit showed that >99% of the radioactive particles were retained in the knee joint even at 96 h post-injection. No significant radioactivity above background was detected in the blood. ConclusionThe promising results warrant further studies on 90Y phosphate particles for use in radiation synovectomy.