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Article

Radiolabeled Divalent Peptidomimetic Vitronectin Receptor Antagonists as Potential Tumor Radiotherapeutic and Imaging Agents

Supporting Info

Thomas D. Harris,* Edward Cheesman, Anthony R. Harris, Richard Sachleben,^† D. Scott Edwards, Shuang Liu,^‡ Judit Bartis,^§ Charles Ellars, Dave Onthank, Padmaja Yalamanchili, Stuart Heminway, Paula Silva, Simon Robinson, Joel Lazewatsky, Milind Rajopadhye, and John Barrett^#

Discovery Research, BristolMyers Squibb Medical Imaging, 331 Treble Cove Road, North, Billerica, Massachusetts 01862

Bioconjugate Chem., 2007, 18 (4), pp 1266–1279

DOI: 10.1021/bc070002+

Publication Date (Web): June 19, 2007

To whom correspondence should be addressed. Phone: 603-893-0031. Fax: 603-898-4605. E-mail: tdharris911@comcast.net.

†

Present address: Momenta Pharmaceuticals, Cambridge, MA.

‡

Present address: Division of Nuclear Pharmacy, Purdue University, West Lafayette, IN.

Present address: ArQule, Woburn, MA.

Present address: AEA Technology QSA, Burlington, MA.

Present address: Astra Zeneca Pharmaceutical, Wilmington, DE.

Present address: VisEn Medical Inc., Woburn, MA.

Present address: Molecular Insight, Cambridge, MA.

Abstract

The integrin receptor α_vβ₃ is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. A radiolabeled α_vβ₃ antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138) was previously shown to exhibit high affinity for integrin α_vβ₃ and high selectivity versus other integrin receptors. ¹¹¹In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and produced excellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and their evaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of the spacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteic acid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays, and biodistribution studies using the ¹¹¹In-labeled derivatives were carried out in the c-neu Oncomouse model. All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight ¹¹¹In derivatives exhibited blood clearance that was faster than ¹¹¹In-TA138 at 24 h postinjection (PI). All divalent agents exhibited tumor uptake and retention at 24 h PI that was higher than ¹¹¹In-TA138. Tumor/organ ratios were improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver, with the agents having intermediate-length spacers (29−43 Å) showing the largest improvement. As an example, ¹¹¹In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney, 7.29; liver, 8.51. A comparison of therapeutic indices for ⁹⁰Y-TA138 and ¹⁷⁷Lu-15 indicate an improved therapeutic index for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalent effect are discussed.