Dataset Information

Functional, Aromatic, and Fluorinated Monothiosemicarbazones: Investigations into Their Structures and Activity toward the Gallium-68 Incorporation by Microwave Irradiation.

ABSTRACT: We report on the synthesis and spectroscopic characterization of a new series of coordinating monothiosemicarbazones incorporating aromatic backbones, featuring O/N/S donor centers monosubstituted with different aliphatic, aromatic, fluorinated, and amine-functionalized groups at their N centers. Their ability to bind metal ions such as Zn(II) and Ga(III) was explored, and the formation of two different coordination isomers of the Zn(II) complex was demonstrated by X-ray diffraction studies using synchrotron radiation. These studies showed the planar geometry for the coordinated mono(thiosemicarbazone) ligand and that the metal center can adopt either a heavily distorted tetrahedral Zn center (placed in an N/S/S/N environment, with CN = 4) or a pseudo-octahedral geometry, where the Zn(II) center is in the O/N/S/S/N/O environment, and CN = 6. Furthermore, 2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide (MTT) assays and cellular imaging in living cells were subsequently performed in two different cancer cell lines: PC-3 (a standard cell line derived from a bone metastasis of a stage IV prostate cancer) and EMT6 (a commercial murine mammary carcinoma cell line). The radiolabeling of new functional and aromatic monothiosemicarbazones with either gallium-68 (under pH control) or fluorine-18 is discussed. The potential of this class of compounds to act as synthetic scaffolds for molecular imaging agents of relevance to positron emission tomography was evaluated in vitro, and the cellular uptake of a simultaneously fluorinated and [⁶⁸Ga]-labeled mono(thiosemicarbazone) was investigated and is reported here.

SUBMITTER: Sarpaki S

PROVIDER: S-EPMC9088960 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Functional, Aromatic, and Fluorinated Monothiosemicarbazones: Investigations into Their Structures and Activity toward the Gallium-68 Incorporation by Microwave Irradiation.

Sarpaki Sophia S Cortezon-Tamarit Fernando F Exner Rüdiger Maria RM Song Kexin K de Aguiar Sara Raquel Mota Merelo SRMM Ge Haobo H Pourzand Charareh C Paisey Stephen James SJ Kociok-Köhn Gabriele G Dilworth Jonathan Robin JR Carroll Laurence L Pascu Sofia Ioana SI

ACS omega 20220411 16

We report on the synthesis and spectroscopic characterization of a new series of coordinating monothiosemicarbazones incorporating aromatic backbones, featuring O/N/S donor centers monosubstituted with different aliphatic, aromatic, fluorinated, and amine-functionalized groups at their N centers. Their ability to bind metal ions such as Zn(II) and Ga(III) was explored, and the formation of two different coordination isomers of the Zn(II) complex was demonstrated by X-ray diffraction studies usin ...[more]

PMID: 35559172

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Project description:Gallium-68 (68Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression. 68Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex 68Ga3+. Ideally, the chelator will rapidly, quantitatively and stably coordinate 68Ga3+ at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based 68Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with 68Ga3+ is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for 68Ga3+ under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5-50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective 68Ga3+ chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for 68Ga3+ complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of 68Ga-biomolecules for molecular PET imaging. LC-MS and 1H, 13C{1H} and 71Ga NMR studies of HBED complexes of Ga3+ showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral [Ga(HBED)(H2O)], with HBED coordinated in a pentadentate N2O3 mode, with only one phenolic group coordinated to Ga3+, and the remaining coordination site occupied by a water molecule.

Project description:ImportanceNeuroendocrine tumors (NETs) express somatostatin receptors, which can be targeted with radiolabeled peptides. In a variety of solid tumors, radioguided surgery (RGS) has been used to guide surgical resection. Gallium 68 (68Ga) dota peptides have been shown to be more accurate than other radioisotopes for detecting NETs. A pilot study previously demonstrated the feasibility and safety of 68Ga-dotatate RGS for patients with NETs.ObjectiveTo evaluate what intraoperative techniques and thresholds define positive lesions that warrant resection during 68Ga-dotatate RGS.Design, setting, and participantsThis prospective cohort study, conducted between October 23, 2013, and February 14, 2018, included 44 patients with NETs who underwent 68Ga-dotatate RGS.InterventionGallium 68-dotatate RGS.Main outcomes and measuresThe in vivo and ex vivo tumor to background ratio (TBR) was assessed for resected lesions and correlated with the histopathologic findings.ResultsForty-four patients (22 women and 22 men; mean [SD] age, 51.0 [13.7] years) had 133 lesions detected on preoperative imaging scans, with a diagnosis of a pancreatic NET (19 of 44 [43%]), gastrointestinal NET (22 of 44 [50%]), and pheochromocytoma or paraganglioma (3 of 44 [7%]). The TBR was obtained by normalizing to the omentum (106 of 133 [79.7%]) or other solid organs (27 of 133 [20.3%]). The omentum had a significantly lower mean (SD) count than other solid organs for background count activity 3 hours after injection (22.1 [17.0] vs 34.5 [39.0]; P < .001). The lesions containing NETs had a higher TBR than those that did not contain NETs (18.9 vs 4.4; P < .001). On a receiver operating characteristic curve analysis, a TBR of 2.5 had a sensitivity of 90% and a specificity of 25%, and a TBR of 16 had a sensitivity of 54% and a specificity of 81%.Conclusions and relevanceA TBR of 2.5 or greater is a highly sensitive threshold for indicating a lesion to be consistent with a NET on histologic findings and thus warranting surgical resection. The omentum should be used as the background count activity for 68Ga-dotatate RGS for patients with abdominal NETs.

Dataset Information

Functional, Aromatic, and Fluorinated Monothiosemicarbazones: Investigations into Their Structures and Activity toward the Gallium-68 Incorporation by Microwave Irradiation.

Publications

Functional, Aromatic, and Fluorinated Monothiosemicarbazones: Investigations into Their Structures and Activity toward the Gallium-68 Incorporation by Microwave Irradiation.

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