Synthesis, characterization and pre-clinical evaluation of (99m) Tc-tricarbonyl complexes as potential myocardial perfusion imaging agents.

Myocardial perfusion imaging is an established Nuclear Medicine investigation. Current myocardial perfusion imaging agents sestamibi and tetrofosmin have number of drawbacks; low heart uptake coupled with uptake into the surrounding tissues leads to a poorer image quality. There is a need for continued research into designing and evaluating potentially superior myocardial imaging agents. Tri-carbonyl-technetium and rhenium complexes were prepared by combination with mono-dentate and bi-dentate ligands. Complexes were characterized by HPLC, MAS, nuclear magnetic resonance, infrared, single-crystal X-ray diffraction and partition coefficient determinations. (99m) Tc(CO)3 complexes were administered intravenously to Sprague Dawley rats, and tissue distribution studies were carried out at 15 min and 1 h p.i. Radiochemical purity was assessed as >90%. 1-10-phenanthroline, 2,2'-bipyridine and imidazole complexes gave the highest heart uptake. The percentage injected dose per gram (n = 3) at 1 h for 1-10-phenanthroline/imidazole was blood 0.21 ± 0.01, heart 1.12 ± 0.11, kidney 3.61 ± 1.13, liver 0.62 ± 0.06, lung 0.28 ± 0.12, spleen 0.24 ± 0.05, small intestine contents 1.87 ± 0.92; and for 2,2'-bipyridine /imidazole was blood 0.23 ± 0.02, heart 1.07 ± 0.18, kidney 3.31 ± 1.28, liver 0.56 ± 0.09, lung 0.14 ± 0.02, spleen 0.2 ± 0.1, small intestine content 1.05 ± 0.48. Further investigation to evaluate more complexes based on 1,10-phenanthroline, 2,2'-bipyridine and imidazole derivatives could potentially lead to agents with an increased heart uptake and faster clearance from the liver and gastrointestinal tract.

Evaluation of 99mTc(CO)5I as a potential lung perfusion agent.

INTRODUCTION: The use of (99m)Tc-macroggregated albumin for lung perfusion imaging is well established in nuclear medicine. However, there have been safety concerns over the use of blood-derived products because of potential contamination by infective agents, for example, Variant Creutzfeldt Jakob Disease. Preliminary work has indicated that Tc(CO)(5)I is primarily taken up in the lungs following intravenous administration. The aim of this study was to evaluate the biodistribution and pharmacokinetics of (99m)Tc(CO)(5)I and its potential as a lung perfusion agent. METHODS: (99m)Tc(CO)(5)I was synthesized by carbonylation of (99m)TcO(4-) at 160 atm of CO at 170 degrees C in the presence of HI for 40 min. Radiochemical purity was determined by HPLC using (99)Tc(CO)(5)I as a reference. (99m)Tc(CO)(5)I was administered by ear-vein injection to three chinchilla rabbits, and dynamic images were acquired using a gamma camera (Siemens E-cam) over 20 min. Imaging studies were also performed with (99m)Tc-labeled macroaggregated albumin ((99m)Tc-MAA) and (99m)TcO(4-) for comparison. (99m)Tc(CO)(5)I was administered intravenously to Sprague-Dawley rats, and tissue distribution studies were obtained at 15 min and 1 h postinjection. Comparative studies were performed using (99m)Tc-MAA. RESULTS: Radiochemical purity, assessed by HPLC, was 98%. The retention time was similar to that of (99)Tc(CO)(5)I. The dynamic images showed that 70% of (99m)Tc(CO)(5)I appeared promptly in the lungs and remained constant for at least 20 min. In contrast, (99m)TcO(4-) rapidly washed out of the lungs after administration. As expected (99m)Tc-MAA showed 90% lung accumulation. The percentage of injected dose per gram of organ +/-S.D. at 1 h for (99m)Tc(CO)(5)I was as follows: blood, 0.22+/-0.02; lung, 12.8+/-2.87; liver, 0.8+/-0.15; heart, 0.15+/-0.01; kidney, 0.47+/-0.08. The percentage of injected dose per organ +/-S.D. at 1 h was as follows: lung, 22.47+/-2.31; liver, 10.53+/-1.8; heart, 0.18+/-0.01; kidney, 1.2+/-0.17. Tissue distribution studies with (99m)Tc-MAA showed 100% lung uptake. CONCLUSION: (99m)Tc(CO)(5)I was synthesized with a high radiochemical purity and showed a high accumulation in the lungs. Further work on the mechanism and optimization of lung uptake of (99m)Tc-pentacarbonyl complexes is warranted.

Gamma-linoleic acid and ascorbate improves skeletal ossification in offspring of diabetic rats.

Maternal diabetes causes a range of complications in offspring, including reduced skeletal ossification. This study examined whether feeding gamma-linoleic acid (GLA) and ascorbate, alone or in combination, to diabetic pregnant rats improves skeletal development in their offspring. In addition, Ca(2+) concentration was monitored in maternal plasma and fetal tissue, as well as placental mRNA expression of calbindin-D(9k). Female rats rendered diabetic with streptozotocin were fed GLA (500 mg/kg/d), ascorbate (290 mg/kg/d), ascorbyl-GLA (790 mg/kg/d), or GLA and ascorbate (500 and 290 mg/kg/d, respectively) throughout pregnancy. Fetal skeletons were studied after alizarin red staining. Fewer ossification centers were observed in offspring of diabetic rats compared with offspring of control rats (68 +/- 4% of control, p = 0.01). An almost complete restoration of ossification occurred with all the treatments (92-95 +/- 3% of control). The effects of treatment on fetal ossification could not be explained by altered maternal plasma Ca(2+) concentrations or by mRNA expression of the placental Ca(2+)-transporting protein calbindin-D(9K). We conclude that GLA and/or ascorbate treatment was effective against diabetes-induced fetal ossification defects by a mechanism not related to placental Ca(2+) supply.