Design, synthesis, and evaluation of radiolabeled integrin αvβ3 receptor antagonists for tumor imaging and radiotherapy

The goal of this research is the development of tumor imaging and radiotherapeutic agents based on targeting of the integrin alpha(v)beta(3) (vitronectin receptor). Macrocyclic chelator DOTA has been conjugated to peptidomimetic vitronectin receptor antagonist SH066 to give TA138. TA138 and Y-89-TA138 retain antagonist properties and high affinity for integrin alpha(v)beta(3) (IC50 = 12 and 18 nM, respectively), and good selectivity versus integrin alpha(IIb)beta(3) (IC50 > 10,000 nM). TA138 forms stable complexes with In-111 and Y-90 in >95% RCP. In-111-TA138 demonstrates high tumor uptake in the c-neu Oncomouse((R)) (Charles River Laboratories [Charles River, Canada]) mammary adenocarcinoma model (9.39% ID/g at 2 hours PI) and low background activity. Blood clearance is rapid and excretion is renal. Tumors are visible as early as 0.5 hours PI. Radiotherapy studies in the c-neu Oncomouse((R)) model demonstrated a slowing of tumor growth at a dose of 15 mCi/m(2), and a regression of tumors at a dose of go mCi/m(2).