DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

Abstract

Abstract.Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2-3 h of externalization a plateau is reached, indicating a steadystate situation explained by reactivation of the receptors followed by re-endocytosis. Biodistribution studies in CA 20948 tumour-bearing rats showed rapid clearance from all sstr-negative tissues except the kidneys. At 4 h the uptake of [ 111 In]DOTA-NOC in the tumour and sstr-positive tissues, such as adrenals, stomach and pancreas, was three to four times higher than that of [ 111 In]DOTA-TOC. Differential blocking studies indicate that this is at least partially due to the uptake mediated by sstr3 and sstr5. These very promising preclinical data justify the use of this new radiopeptide for imaging and potentially internal radiotherapy studies in patients.

Radiolabeled somatostatin receptor antagonists are preferable to agonists forin vivopeptide receptor targeting of tumors

“…In the in vivo model of an sst 3 -expressing tumor, we have compared the biodistribution of the sst 3 antagonist, 111 In-DOTAsst 3 -ODN-8, with that of an established agonist, 111 In-DOTA-NOC (19)(20)(21). nat In-DOTA-NOC has high binding affinity to sst 3 receptors in vitro (19) and efficiently triggers the sst 3 internalization into HEK-sst 3 cells.…”

“…Their radiolabeled derivatives may be used as antagonist radioligands in case the high affinity-binding and antagonistic properties are retained after conjugation with a chelator [e.g., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)] and 111 In-complexation. Third, well characterized radiolabeled agonists, which can label sst 3 receptors in vitro and in vivo, have recently been described (19)(20)(21) 3 . The reference agonist nat In-DOTA-NOC has comparable sst 3 -binding affinity, whereas the sst 2 -selective analog ( nat In-DTPA-TATE), used in its 111 In-labeled form as a negative control for sst 3 -expressing tissues in the biodistribution assays, shows high sst 2 but no sst 3 affinity ( Table 1).…”

Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT Within Patients with Gastroenteropancreatic Neuroendocrine Tumors

“…The peptide-chelator conjugates [DOTA,Tyr 3 ]-octreotate (DOTATATE) and [DOTA,1-Nal 3 ]-octreotide (DOTANOC) were synthesized by standard Fmoc solid-phase synthesis on 2-chlorotritylchloride resin on a peptide synthesizer (Switch 24; Rink CombiChem Technologies), according to a general procedure described previously (6). 68 Ga-DOTATATE and 68 Ga-DOTANOC were labeled under sterile conditions in an isolator using a modification of the method described by Zhernosekov et al (16) and Shastry et al (17).…”

“…Gastrinomas, ileal carcinoids, and VIPomas express sst 2 or sst 5 with an incidence of almost 100% (1). [DOTA, 1-Nal 3 ]-octreotide (DOTANOC) is a peptide that promises to target a broader range of somatostatin subtype receptors, including sst 2 , sst 3 , and sst 5 (6,7). Preliminary results in single patients suggest that this new radiopeptide locates more metastases than do sst 2 -specific tracers (7,8).…”

68Ga-Labeled Radiopharmaceuticals for Positron Emission Tomography

“…In particular, 68 Ga-DFO-octreotide injected into rats bearing SSTRpositive pancreatic tumors demonstrated selective binding to tumor sites with a tumor to background ratio (T/B) of 5 [32]. Subsequently, several DOTA-SST analogues were evaluated in vivo, and 68 Ga-DOTA-TOC and 68 Ga-DOTA-NOC were found to be the most promising [33][34][35][36].…”