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

• Main Authors: Sofia Koustoulidou (Author), Maryana Handula (Author), Corrina de Ridder (Author), Debra Stuurman (Author), Savanne Beekman (Author), Marion de Jong (Author), Julie Nonnekens (Author), Yann Seimbille (Author)
• Format: Book
• Published: MDPI AG, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 (<b>8a</b> and <b>8b</b>), 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. [¹⁷⁷Lu]Lu-<b>8a</b> and [¹⁷⁷Lu]Lu-<b>8b</b> were obtained with high radiochemical purity (>97%) and demonstrated excellent stability in PBS and mouse serum (>95%). [¹⁷⁷Lu]Lu-<b>8a</b> showed better affinity towards human albumin compared to [¹⁷⁷Lu]Lu-<b>8b</b>. Further, <b>8a</b> and <b>8b</b> 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 [¹⁷⁷Lu]Lu-<b>8a</b> and [¹⁷⁷Lu]Lu-JR11 at 4, 24, 48, and 72 h post-injection, but no tumor uptake was observed for [¹⁷⁷Lu]Lu-<b>8b</b>. Ex vivo biodistribution studies revealed high and increasing tumor uptake for [¹⁷⁷Lu]Lu-<b>8a.</b> However, its extended blood circulation led to an unfavorable biodistribution profile for radionuclide therapy.

Item Description

10.3390/ph15091155
1424-8247