These results demonstrate successful 99mTc labeling of a peptidomimetic integrin antagonist that accumulated in a tumor via receptor-specific binding. At 1 hr, the tumor uptake was 0.47% injected dose (ID)/g, but decreased to 0.12% ID/g when co-injected with an excess amount of PIA, indicating that accumulation was receptor mediated. At 20 min, the tumor-toblood ratio was 1.8.

In tumor bearing mice, 99mTc(CO) 3-ADA-PIA accumulated rapidly in a receptor-positive tumor with a peak uptake at 20 min, and rapid clearance from blood occurring primarily through the hepatobiliary system.

99mTc(CO) 3-ADA-PIA was stable in phosphate buffer for 21 hr, but at 3 and 6 hr, 7.9 and 11.5% of the radioactivity was lost as histidine, respectively. A separate group of mice were also co-injected with 200 μg of PIA and euthanized at 1 hr to quantify tumor uptake. The animals were euthanized at 0.33, 1, and 2 hr after injection for the biodistribution study. The mice were administered 99mTc(CO) 3-ADA-PIA intravenously. Biodistribution analysis was performed in nude mice (n = 5 per time point) bearing receptor-positive M21 human melanoma xenografts. Using gradient C-18 reverse-phase HPLC, the radiochemical purity of 99mTc(CO) 3-ADA-PIA (retention time, 10.5 min) was confirmed to be > 95%. The product, PIA-aminodiacetic acid (ADA), was radiolabeled with +1, and purified sequentially on a Sep-Pak C-18 cartridge followed by a Sep-Pak QMA anion exchange cartridge. PIA was reacted with tris-succinimidyl aminotriacetate (TSAT) (20 mM) as a PIA per TSAT. The aim of this research was to label a peptidomimetic integrin α vβ 3 antagonist (PIA) with 99mTc(CO) 3 and to test its receptor targeting properties in nude mice bearing receptor-positive tumors. The selective targeting of an integrin α vβ 3 receptor using radioligands may enable the assessment of angiogenesis and integrin α vβ 3 receptor status in tumors.

Mac mod analytical