Novel Structural Modification Based on Evans Blue Dye to Improve Pharmacokinetics of a Somastostatin-Receptor-Based Theranostic Agent

The development of somastatin (SS) peptide analogues for the detection and treatment of neuroendocrine tumors has been successful with the recent FDA approval of 68Ga–DOTA–TATE and 177Lu–DOTA–TATE. The structure of these peptide constructs contains the peptide binding motif that binds to the receptor with high affinity, a chelator to complex the radioactive metal, and a linker between the peptide and chelator. However, these constructs suffer from rapid blood clearance, which limits their tumor uptake. In this study, this design has been further improved by incorporating a modification to control the in vivo pharmacokinetics. Adding a truncated Evans Blue (EB) dye molecule into the construct provides a prolonged half-life in blood as a result of its low micromolar affinity to albumin. We compared 177Lu–DOTA–TATE to the modified 177Lu Evans Blue compound (177Lu–DMEB–TATE), in vitro and in vivo in mice bearing A427-7 xenografts. The tumor uptake of 177Lu–DMEB–TATE was significantly greater than the uptake of 177Lu–DOTA–TATE in the biodistribution and SPECT-imaging studies. The therapeutic effect of the 177Lu–DMEB–TATE construct was superior to the that of the 177Lu–DOTA–TATE construct at the doses evaluated.