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

Abstract

The integrin receptor alpha(v)beta(3) is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. Radiolabeled alpha(v)beta(3) 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 alpha(v)beta(3) antagonists belonging to the quinolin-4-one class of peptidomimetics, and their radiolabeling with (99m)Tc (for HYNIC) and (111)In (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 alpha(v)beta(3) and high selectivity versus receptors alpha(IIb)beta(3), alpha(v)beta(5), alpha(5)beta(1). Biodistribution of the radiolabeled compounds was evaluated in the c-neu Oncomouse mammary adenocarcinoma model. DOTA conjugate (111)In-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 (111)In-TA138 and the other radiolabeled compounds of this study are presented and discussed. A scintigraphic imaging study with (111)In-TA138 showed a clear delineation of the tumors and rapid clearance of activity from nontarget tissues.

The Use of One-Bead One-Compound Combinatorial Library Technology to Discover High-Affinity αvβ3 Integrin and Cancer Targeting Arginine-Glycine-Aspartic Acid Ligands with a Built-in Handle

“…Peptides with an RGD motif or peptidomimetics against αvβ3 integrin (46) have been utilized as probes for tumor imaging and for monitoring therapeutic response to anti-angiogenic agents. We focused on RGD peptide ligands and compared LXW7 with several other well-known RGD ligands.…”

Minute dosages of ανβ3‐targeted fumagillin nanoparticles impair Vx‐2 tumor angiogenesis and development in rabbits

“…High uptake of the radioligand was measured 71 h postinjection in the U87MG tumor model, suggesting that the agent may be useful for characterizing the pharmacokinetics, tumor targeting efficacy, dose optimization, and dose interval of Abegrin alone or Abegrin chemotherapeutics or radiotherapeutic conjugates. Numerous radiolabeled ␣ v ␤ 3 -integrin antagonist peptides (34 -36) and peptidomimetics (37)(38)(39) have been explored as tumor vasculature targeting imaging agents. Beta-emitting nuclide-peptide conjugates or integrin-targeted liposomes have found modest effectiveness against some cancers (34,39), but these have found limited clinical success, due to limited efficacy and radioactive dose-limiting toxicity.…”

Identification and Characterization of a Peptide with Affinity to Head and Neck Cancer

“…Such changes have also been found in HNSCC, for which many integrin receptors are downregulated, except for a v b 3 , which is overexpressed; other integrins show de novo expression, as has been demonstrated for a v b 6 and a 6 b 4 dimers (20,21). RGD motif peptides and various modified versions of RGD containing molecules such as peptidomimetics, pseudopeptides, and disintegrins (venom-derived) have been studied for their usefulness for cancer treatment or disease-related angiogenesis treatment (peptidomimetics (22), pseudopeptides (23), venom (24)). Cilengitide (cyclo(Arg-Gly-Asp-D-Phe-[NMe]Val)) (Merck KGaA) is a peptide in phase I and II trials dealing with a variety of solid tumors and neovascular endothelial cells (25,26).…”