Radiolabeled bicyclic somatostatin-based analogs: a novel class of potential radiotracers for SPECT/PET of neuroendocrine tumors

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. The bicyclic peptides were synthesized by standard solid-phase peptide synthesis. DOTA was coupled to the resin-assembled peptide for labeling with (177)Lu and (68)Ga. Binding affinity and receptor subtype profile were determined using human ssts. Ca(2+) flux, internalization, and efflux were studied in human embryonic kidney (HEK)-sst(2) and HEK-sst(3) cell lines. Biodistribution and PET/CT studies were performed in corresponding nude mice models. Some of the new analogs showed high affinity for sst(2) and sst(3) and moderate affinity for sst(1), sst(4), and sst(5), 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. (177)Lu-AM3 showed high and receptor-mediated uptake in vivo in sst(2) and sst(3) 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 (68)Ga-AM3 at 1 h after injection were characterized by clear localization of the tumor, visualization of the kidneys, and negligible background. 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 (177)Lu/(68)Ga-AM3 make this peptide an excellent candidate as an imaging--and especially as a PET--radiotracer.