Radiolabeled Bicyclic Somatostatin-Based Analogs: A Novel Class of Potential Radiotracers for SPECT/PET of Neuroendocrine Tumors

Journal of Nuclear Medicine

Andreas Mueller¹  Maria-Luisa Tamma¹  Melpomeni Fani¹  Renzo Cescato¹  Guillaume Nicolas¹  Helmut R. Maecke¹  Jean Claude Reubi¹  Hans R. Rink¹ 

关键词: bicyclic somatostatin analogs;    somatostatin receptor subtypes;    ⁶⁸Ga-PET/CT;    receptor targeting;   

DOI  :  10.2967/jnumed.110.076695

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

A variety of radiolabeled somatostatin analogs have been developed for targeting of somatostatin receptor (sst)–positive tumors. Bicyclic somatostatin-based radiopeptides have not been studied yet. Hypothesizing that the introduction of conformational constraints may lead to receptor subtype selectivity or may help to delineate structural features determining pansomatostatin potency, we developed and evaluated first examples of this new class of potential radiotracers for imaging or therapy of neuroendocrine tumors. Methods: The bicyclic peptides were synthesized by standard solid-phase peptide synthesis. DOTA was coupled to the resin-assembled peptide for labeling with 177Lu and 68Ga. Binding affinity and receptor subtype profile were determined using human ssts. Ca2+ flux, internalization, and efflux were studied in human embryonic kidney (HEK)-sst2 and HEK-sst3 cell lines. Biodistribution and PET/CT studies were performed in corresponding nude mice models. Results: Some of the new analogs showed high affinity for sst2 and sst3 and moderate affinity for sst1, sst4, and sst5, while exhibiting agonistic properties. The analog AM3, comprising an octreotide ring and a head-to-tail–coupled Arg-diaminobutyric acid(DOTA) cycle, showed the highest receptor affinity and agonist potency. 177Lu-AM3 showed high and receptor-mediated uptake in vivo in sst2 and sst3 tumors with low background. Kidneys were the only other tissue accumulating radioactivity that could be reduced by a preinjection of lysine. PET/CT studies of 68Ga-AM3 at 1 h after injection were characterized by clear localization of the tumor, visualization of the kidneys, and negligible background. Conclusion: The high rigidity of these new bicyclic somatostatin-based radiopeptides led to agonistic ligands with good affinity for all 5 ssts. The pharmacokinetic data of 177Lu/68Ga-AM3 make this peptide an excellent candidate as an imagingand especially as a PETradiotracer.

【 授权许可】

Unknown