PRECLINICAL EVALUATION AND PHASE-I CLINICAL-TRIAL OF A TC-99M-LABELEDSYNTHETIC-POLYMER USED IN BLOOD-POOL IMAGING

OBJECTIVE. To obtain initial data on the safety and efficacy of a nove l polymeric, synthetic blood pool contrast agent {O-monomethoxypoly(et hylene l}poly(N-epsilon-L-lysyl{Tc-99m}diethylenetriamine pentaacetate monoamide, we performed a preclinical evaluation and phase 1 clinical trial under an investigator-sponsored investigational new drug applic ation. MATERIALS AND METHODS. Methoxypoly(ethylene glycol)ethylenetria minopentaacetic acid was formulated into a kit containing the polymer, stannous chloride, and a buffer. Kits were stored in frozen form for subsequent labeling with technetium-99m. Acute and subacute toxicity s tudies were carried out in rats and rabbits. Healthy human volunteers (n = 6) were then enrolled in a prospective, open-label phase 1 clinic al study. RESULTS. Animal studies showed no signs of acute or subacute toxicity at doses 280 times the proposed dose for humans. In the clin ical trial with humans, no significant abnormalities of laboratory val ues, ECG findings, or hemodynamic parameters were seen. One volunteer experienced facial flushing and palpitations. Four volunteers showed t ypical blood pool biodistribution, with a blood half-life of 20.6 +/- 2.3 hr.At 24 hr after administration, 22.1% +/- 2.5% of the injected d ose had been excreted through the kidneys. Two other volunteers showed a different biodistribution (primarily to liver and spleen), presumab ly associated with labeling instability. CONCLUSION. Synthetic methoxy poly(ethylene glycol)-grafted polymers can have long circulation times in humans. Pharmaceuticals based on such polymers are expected to hav e clinical applications in cardiovascular imaging, gastrointestinal bl eeding studies, and capillary leak imaging.