Synthesis, in vitro screening and in vivo evaluation of cyclic RGD analogs cyclized through oxorhenium and oxotechnetium coordination

A library of RGD tripeptide analogs cyclized through oxorhenium coordination by an NS2/S chelation motif was synthesized. Screening towards integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 6 oxorhenium complexes that bind to integrin αVβ3 in the submicromolar range. In vivo evaluation of five of the corresponding oxotechnetium complexes using nude mice bearing a U87MG human tumor xenograft showed a significant and specific accumulation of radioactivity inside the tumor. The best results in vivo were obtained with complexes Tc-16 and Tc-50 that displayed a higher tumor accumulation and a lower distribution in other tissues relative to a reference cyclopentapeptide tracer.

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► Synthesis of a library of 55 oxorhenium complexes to mimic RGD peptides.
► Identification of 6 submicromolar integrin antagonists by screening of the library.
► Five of the selected complexes exhibited satisfactory stabilities in murine plasma.
► Two complexes accumulated specifically in U87MG tumors relative to healthy tissues.