Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors

Introduction: The alpha(v)beta(3) integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of alpha(v)beta(3)-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with alpha(v)beta(3)-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with Tc-99m. In an effort to begin to address this limitation, we evaluated the tumor uptake of Tc-99m-NC100692, a cyclic RGD peptide that binds to alpha(v beta 3) with similar to 1-nM affinity, in an alpha(v)beta(3)-positive tumor model as well as its in vivo specificity. Methods: MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for alpha(v)beta(3), to block and displace Tc-99m-NC100692 in an orthotopic U87 glioma tumor. The specificity of Tc-99m-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of Tc-99m-NC100692 with that of the non-specific structural analogue Tc-99m-AH-111744 and by blocking uptake of Tc-99m-NC100692 with excess unlabeled NC100692. Results: MicroSPECT imaging studies demonstrated that uptake of Tc-99m-NC100692 in the intracranial tumor model was both blocked and displaced by the alpha(v)beta(3)-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of Tc-99m-NC100692 at 1 h post-injection was 2.8 +/- 0.7% ID/g compared to 0.38 +/- 0.1% ID/g for Tc-99m-AH-111744 (p < 0.001). Blocking Tc-99m-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 +/- 0.3% ID/g (p = 0.01). Conclusion: These results confirm that Tc-99m-NC100692 does, in fact, target the alpha(v)beta(3) integrin and may, therefore, be useful in identifying patients prior to anti-alpha(v)beta(3) therapy as well as monitoring the response of these patients to therapy. (C) 2013 Elsevier Inc. All rights reserved.