Abstract
1445
Objectives: The aim was to radiolabel a peptidomimetic integrin αvβ3 antagonist with 99mTc and selectively target integrin αvβ3-expressing tumors. Methods: HYNIC-NHS was conjugated to the amino end group of 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonylamino-β-alanine hydrochloride (IAC), a second generation hydrophobic derivative. The IAC-HYNIC was labeled with 99mTc using EDDA as co-ligand, and purified on a Sep-Pak C-18 cartridge. The receptor-binding activity was confirmed by incubating at 37°C for 3 hrs with αvβ3 at a molar excess and analyzing with size exclusion HPLC. Nude mice (n = 5 per time point) implanted with αvβ3-expressing M21 human melanoma were injected i.v. with the 99mTc labeled product (6.25 μCi/12.1 pg in 0.2 ml PBS containing 1% BSA) and were euthanized at 0.33, 1 and 2 hr after injection. A group of mice was also coinjected with 200 μg of a peptidomimetic antagonist. Results: The 99mTc product bound to αvβ3 in vitro with 55.2% bound to αvβ3 at 0.4 μM whereas the binding was blocked by a molar excess of cold αvβ3 antagonist. It accumulated rapidly in the receptor-positive tumor with uptake values of 3.47 ± 0.33, 2.87 ± 0.55 and 2.88 ± 0.29% ID/g at 0.33, 1 and 2 hr, respectively. It was excreted primarily via the renal system with 56.0 ± 2.43% ID retained in the whole-body at 20 min and 34.5 ± 2.18% at 2 hr. The tumor-to-background ratios increased over time: The ratios were 0.9, 0.7, 0.7, 0.5, 0.7, 1.9, 0.5, 0.7, 1.3 and 3.0 for blood, spleen, liver, kidney, lung, heart, stomach, intestine, bone and muscle, respectively, at 20 min, and at 2 hr, the corresponding ratios became 2.2, 1.3, 1.0, 0.9, 1.5, 3.2, 0.4, 0.6, 2.5 and 4.7. The coinjection of cold antagonist decreased the tumor uptake to 0.68 ± 0.06 at 1 hr, indicating that the tumor uptake was receptor mediated. Conclusions: The HYNIC labeling method using EDDA as co-ligand formed 99mTc labeled IAC that was retained in the receptor-positive tumor while being excreted rapidly from the whole-body, and warrants further investigation for tumor imaging.
- Society of Nuclear Medicine, Inc.