Preparation and Biological Evaluation of [^99mTc/EDDA/Tricine/HYNIC⁰, BzThi³]-Octreotide for Somatostatin Receptor-Positive Tumor Imaging

Abstract

Somatostatin-derived analogues play an important role in the diagnosis and treatment of neuroendocrine tumors. The aim of this study was to evaluate a new somatostatin analogue designed for labeling with (99m)Tc: [6-hydrazinopyridine-3-carboxylic acid (HYNIC(0)), β-(3-benzothienyl)-Ala (BzThi(3))]-octreotide ([HYNIC]-BOC), using ethylenediamine-N,N'-diacetic acid (EDDA) and tricine as coligands. Synthesis was performed on a solid phase using a standard Fmoc strategy. The HYNIC-peptide conjugate was radiolabeled with (99m)Tc and characterized by ITLC and high-performance liquid chromatography (HPLC). In vitro studies were carried out in sstr2 expressing AR4-2J cell lines. In vivo distribution studies were performed in rats bearing the AR4-2J tumor. The radiolabeled complex could be prepared at high-specific activities and >95% radiochemical yield as determined by HPLC. The peptide conjugate showed high-affinity binding for sstr2. The radioligand showed high and specific internalization into AR4-2J cells (18.19%±0.21% at 4 hours). In vivo distribution studies in rats bearing tumor have shown a receptor-specific uptake of radioactivity in somatostatin receptor-positive organs. After 4 hours, uptake in the AR4-2J tumor was 1.71%±0.36% injected dose per gram tissue (%ID/g). These data show that [(99m)Tc/EDDA/Tricine/HYNIC(0), BzThi(3)]-octreotide is a specific radioligand for the somatostatin receptor-positive tumors and is a suitable candidate for clinical studies.

Synthesis and evaluation of a 99mTc‐labeled tubulin‐binding agent for tumor imaging

“…First, the acetamide moiety of colchicine ( 1 ) was protected ( 2 ), deacetylated ( 3 ), and deprotected ( 4 ) with a final yield of 40% using a strategy based on an earlier reported methodology . Then, the obtained deacetylcolchicine was allowed for conjugation with a 6‐ tert ‐butoxycarbonyl‐hydrazinopyridine‐3‐carboxylic acid (Boc‐HYNIC) as a known protected HYNIC‐based prochelator using a standard peptide coupling methodology to generate compound 5 . Finally, mild acidolysis with trifluoroacetic acid (TFA) removed the protecting group and the required HYNIC‐colchicine conjugate ( 6 ) was revealed without demethylation of the tropolone methoxy function (a potential outcome in acidic environments) as indicated by retention of the associated resonances in the 1 H NMR spectrum (δ: 3.53; s, 3H).…”

“…A variety of chelators have been used as a bifunctional chelating agent (BFCA) in labeling proteins, peptides, and other biologically active molecules by 99m Tc . Among these, HYNIC is one of the candidates that can form monodentate diazenido complexes (TcNN–R) with the central metal.…”

“…On the basis of the previous work by various research groups in labeling of peptides with 99m Tc using HYNIC as a chelator, labeling was performed. A stock solution of HYNIC‐colchicine (concentration 0.5 mg/mL) was prepared by dissolving the HYNIC‐colchicine in distilled water.…”

“…In labeling process coligands, tricine and EDDA can be used separately or together via exchange labeling method. We also recently reported the evaluation of some new peptide analogs labeled via bifunctional chelating agents HYNIC and EDDA/tricine as coligands . In continuation of our efforts to create a new 99m Tc‐labeled ligand for tumor targeting, we chose colchicine as a ligand and after modification of its acetamido moiety was conjugated to a bifunctional chelating agent HYNIC, which is known to form a complex with 99m Tc.…”

A99mTc-tricine-HYNIC-labeled peptide targeting the neurotensin receptor for single-photon imaging in malignant tumors

“…We also recently reported the evaluation of a new somatostatin and bombesin analogs labeled via bifunctional chelating agents HYNIC . In continuation of our efforts to create a 99m Tc‐labeled peptide for tumor targeting, in this study, a derivative of NT (8–13) containing HYNIC as a bifunctional chelating ligand was synthesized and labeled with favorable gamma irradiated radionuclide 99m Tc via coligand tricine.…”