Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors.

Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more effective treatment. Therefore, two JR11 analogs ( 8a and 8b ), each carrying an albumin binding domain, were designed to prolong the blood residence time of JR11. Both compounds were labeled with lutetium-177 and evaluated via in vitro assays, followed by in vivo SPECT/CT imaging and ex vivo biodistribution studies. [ 177 Lu]Lu- 8a and [ 177 Lu]Lu- 8b were obtained with high radiochemical purity (>97%) and demonstrated excellent stability in PBS and mouse serum (>95%). [ 177 Lu]Lu- 8a showed better affinity towards human albumin compared to [ 177 Lu]Lu- 8b . Further, 8a and 8b exhibited binding affinities 30- and 48-fold lower, respectively, than that of the parent peptide JR11, along with high cell uptake and low internalization rate. SPECT/CT imaging verified high tumor accumulation for [ 177 Lu]Lu- 8a and [ 177 Lu]Lu-JR11 at 4, 24, 48, and 72 h post-injection, but no tumor uptake was observed for [ 177 Lu]Lu- 8b . Ex vivo biodistribution studies revealed high and increasing tumor uptake for [ 177 Lu]Lu- 8a. However, its extended blood circulation led to an unfavorable biodistribution profile for radionuclide therapy.