Synthesis and biological evaluation of RGD peptides with the 99mTc/188Re chelated iminodiacetate core: highly enhanced uptake and excretion kinetics of theranostics against tumor angiogenesis

Abstract

To develop a companion set of RGD-based agents for diagnostic and radiotherapeutic purposes, facile incorporation of ^99mTc(CO)₃ or ¹⁸⁸Re(CO)₃ into the same precursor produced, respectively, a structurally and functionally matched radiodiagnostic and radiotherapeutic—or theranostic—pair. This work presents the synthesis of two ^99mTc-labeled RGD monomers (4 and 5) along with a ^99mTc-labeled RGD dimer (6) and an investigation of the influence of the small-sized and negatively charged ^99mTc-iminodiacetate (IDA) core on the in vitro and in vivo behavior of these three different RGD analogs for imaging integrin α_vβ₃ expression. Among the three ^99mTc-IDA-RGD analogs, 6 exhibited the highest integrin binding affinity with an IC₅₀ value of 0.5 nM and a tumor uptake with an ID/g value of 12.3 ± 5.15% at 60 min post-injection, whereas liver and intestinal levels remained relatively low with good metabolic stability (>97%), presumably because of the overall negative charge of the radiometal chelating system. Both ^99mTc/¹⁸⁸Re-labeled compounds (6 and 7), which were prepared from the precursor (18), provided a good tumor accumulation and a clearly visible image of the tumor with high contrast, as compared to the contralateral background in the U87-MG xenograft model. These data support the use of ^99mTc- and ¹⁸⁸Re-IDA-D-[c(RGDfK)]₂ as a matched radio-theragnostic pair that can be used to individualize radiotherapy for angiogenesis-dependent cancer.