Structure−Activity Relationships of 111In- and 99mTc-Labeled Quinolin-4-one Peptidomimetics as Ligands for the Vitronectin Receptor: Potential Tumor Imaging Agents

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Abstract
The integrin receptor αvβ3 is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. Radiolabeled αvβ3 antagonists have demonstrated potential application as tumor imaging agents and as radiotherapeutic agents. This report describes the total synthesis of eight new HYNIC and DOTA conjugates of receptor αvβ3 antagonists belonging to the quinolin-4-one class of peptidomimetics, and their radiolabeling with 99mTc (for HYNIC) and 111In (for DOTA). Tethering of the radionuclide−chelator complexes was achieved at two different sites on the quinolin-4-one molecule. All such derivatives maintained high affinity for receptor αvβ3 and high selectivity versus receptors αIIbβ3, αvβ5, α5β1. Biodistribution of the radiolabeled compounds was evaluated in the c-neu Oncomouse mammary adenocarcinoma model. DOTA conjugate 111In-TA138 presented the best biodistribution profile. Tumor uptake at 2 h postinjection was 9.39% of injected dose/g of tissue (%ID/g). Activity levels in selected organs was as follows: blood, 0.54% ID/g; liver, 1.94% ID/g; kidney, 2.33% ID/g; lung, 2.74% ID/g; bone, 1.56% ID/g. A complete biodistribution analysis of 111In-TA138 and the other radiolabeled compounds of this study are presented and discussed. A scintigraphic imaging study with 111In-TA138 showed a clear delineation of the tumors and rapid clearance of activity from nontarget tissues.