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

Abstract

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 177 Lu and 68 Ga. Binding affinity and receptor subtype profile were determined using human ssts. Ca 21 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. Results: 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. 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 177 Lu/ 68 Ga-AM3 make this peptide an excellent candidate as an imaging-and especially as a PET-radiotracer.

PET of Somatostatin Receptor–Positive Tumors Using 64Cu- and 68Ga-Somatostatin Antagonists: The Chelate Makes the Difference

“…The final products, CB-TE2A-LM3, NODAGA-LM3, and DOTA-LM3, were purified by semipreparative HPLC and characterized by electrospray ionization mass spectrometry and RP-HPLC. 68 Ga-NODAGA-LM3 and 68 Ga-DOTA-LM3 were prepared in sodium acetate buffer (0.2 mol/L, pH 4.0), at RT for 10 min (NODAGA-LM3) or at 95°C for 8 min (DOTA-LM3), as described elsewhere (20). 64 Cu and 68 Ga radiopeptides were prepared without any postlabeling purification step.…”

“…The internalization and dissociation rates of 64 Cu-CB-TE2A-LM3 and 64 Cu-NODAGA-LM3 were studied in HEK-sst2 cells seeded in 6-well plates, as described previously (18,20). Briefly, the radiopeptide was added to the medium (0.25 pmol/mL), and the cells were incubated at 37°C.…”

Somatostatin Receptors as Targets for Nuclear Medicine Imaging and Radionuclide Treatment

“…A recent example is the development of bicyclic somatostatin-based radiopeptides, a neglected family of radiopeptides, developed by Fani et al (24). These molecules have fast background clearance and therefore high tumor-to-normal organ ratios.…”

Radiopharmaceuticals for somatostatin receptor imaging

“…One of the first reports describing 68 Ga-and 64 Cu-labeled sst2 antagonists indicated the high potential of these radiopeptides in PET/CT [75]. Translational aspects related to peptide receptor radionuclide therapy (PRRT) and imaging with antagonist were also addressed.…”

“…However, the application of similarly developed 111 In-DOTANOC-ATE (1-NaI [63]. Fani et al (2010) reported the development of bicyclic somatostatin analogs with affinity to sst2, sst3 and sst5, such as AM3 (DOTA-)Tyr-cyclo(DAB-Arg-cyclo(Cys-Phe--D-Trp-Lys-Thr-Cys)) which showed fast background clearance and high tumor to non-tumor ratios which might be ideal for imaging with short lived radionuclides such as 68 Ga [64]. Pan-somatostatin radiopeptides with high affinity binding for all five receptor subtypes have also been developed.…”