Labelling, control and radiopharmacological evaluation of 99mTc-adenosine 5'-diphosphate (99mTc-ADP) as tumour seeking agent.

A study of 99mTc-adenosine-5'-diphosphate (99mTc-ADP) as a radiopharmaceutical for tumour diagnosis is presented. Two different labelling methods, using SnCl2 in alkaline solution and Zn as reducing agents, were developed. Reduction with Sn(II) alkaline solution was the selected method because a lower concentration of ADP (0.5 mg/mL) could be used and a higher radiochemical yield was achieved. A labelled molecule with a radiochemical purity higher than 95%, in vitro stability of at least 6 hours and an over all negative charge was obtained Biodistribution studies carried out in normal mice and rats revealed rapid urinary excretion and no specific accumulation of activity in any other particular organ. This behaviour was similar to that reported for 99mTc-adenosine-5'-triphosphate (99mTc-ATP). Rapid blood clearance, that could be fitted to a bicompartimental model, was also verified. No evidence of in vivo instability was observed. Studies in mice and rats bearing spontaneous mammary adenocarcinomas were performed and the results were compared to those from the 99mTc-ATP studies. Although the tumour models used were not the same, the incorporation of both labelled compounds was very similar. Radioactivity uptake in the tumour and the tumour-to-blood ratio were not notably high. However, a significant increment was observed in the tumour-to-muscle ratio (1.0 +/- 0.2 at 30 minutes to 2.7 +/- 0.4 at 240 minutes). Whole-body autoradiography enabled tumour visualization. Further investigations, including scintigraphic imaging, must be carried to complete the clinical evaluation of 99mTc-ADP as a tumour seeking agent.

99mTc-ADP: a potential agent for in vivo tumor detection.

The possibility of using 99mTc-labelled nucleotides as tumour seeking agents has been proposed by different research groups. We have recently reported the preparation of a 99mTc-ADP complex with a high radiochemical purity (> 95%), good in vitro and in vivo stability and promising biodistribution results when injected in mice bearing spontaneous mammary adenocarcinomas. Here we report the results of further investigations in animals with spontaneous neoplastic processes, including whole-body autoradiography in mice (20 minutes and 60 minutes post injection) and gamma-camera imaging studies in Wistar rats. Dynamic studies (up to 45 minutes) and static images (up to 18 hours) were acquired to determine the pharmacokinetics of 99mTc-ADP and the tumour/muscle and tumour/blood ratios. Blood-pool studies were also performed as a control. Tumours were visualized by autoradiography as was to be expected from the biodistribution studies. Dynamic studies showed a rapid blood clearance and a behaviour that fitted to a tricompartimental model. Radioactivity was rapidly taken up by the kidneys and excreted in the urine. No evidence of in vivo instability of the complex was observed. Tumour uptake reached the maximum values after 20 minutes post-injection. Tumour/blood and tumour/muscle ratios improved over time, enhancing tumour visualization. The best images were obtained after 3 hours post injection. In summary, our studies suggest that 99mTc-ADP is a promising radiopharmaceutical for tumour diagnosis.

Human pharmacokinetics and radiopharmacological studies of the myocardial perfusion agent: technetium (2-carbomethoxy-2-isocyano-propane)6+.

The myocardial perfusion agent technetium (2-carbomethoxy-2-isocyano-propane)6+ (99mTc-CPI) is unique from other cationic technetium isonitrile complexes in that it exhibits moderate washout from the heart and rapid hepatobiliary clearance in animal models and human volunteers. Dynamic imaging and HPLC analysis were performed in humans and guinea pigs to outline the pharmacological basis of its pharmacokinetics. Enzymatic hydrolysis of the terminal ester groups in blood was found to occur at a moderate rate producing new species that have been shown not to accumulate in heart tissue. However, after extraction by the heart, liver or kidneys, the 99mTc-CPI complex undergoes metabolism at a much slower rate than observed in the blood. Differences in hydrolysis rate and products obtained indicate separate mechanisms of hydrolysis occurring in blood and other organs. It is proposed that the heart washout occurring after hydrolysis produces a neutral compound which is no longer retained by the negative cytosolic and mitochondrial membrane potentials in myocardial tissue.