Synthesis of a new bifunctional NODA for bioconjugation with PSMA ligand and one-step Al18F labeling. (15th April 2022)

• Record Type: Journal Article
• Authors: Wang, Sheng; Gai, Yongkang; Li, Mengting; Fang, Hanyi; Xiang, Guangya; Ma, Xiang
• Is Part Of: Bioorganic & medicinal chemistry. Volume 60(2022)
• Publication Date: 2022-04-15
• Subjects: Fluorine-18 -- Aluminum fluoride -- Chelator -- PSMA -- PET; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116687
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Synthesis, characterization and bioconjugation with PSMA ligand of a new bifunctional NODA and MicroPET scan of the Al 18 F labeled peptide in healthy mice. Highlights: A new bifunctional pentadentate AlF-chelator p -SCN-PhPr-NODA was synthesized. The coordination chemistry was investigated by density functional theory calculations. Bifunctional chelator was conjugated to a PSMA targeting moiety Glu-urea-Lys. The conjugated peptide was efficiently labeled with 18 F with high radiochemical purity. In vitro evaluation, biodistribution and MicroPET scan of the labeled peptide. Abstract: The Al 18 F labeling method is a relatively new approach that allows radiofluorination of biomolecules such as peptides and proteins in a one-step procedure and in an aqueous solution. However, instability of the complex of [AlF] 2+ with hexadentate chelator NOTA may attribute to the disassociation of free 18 F − and [Al 18 F] 2+ and accumulation in bone. In this study, we designed and synthesized a new bifunctional pentadentate AlF-chelator p -SCN-PhPr-NODA as well as its nitro form p -NO2 -PhPr-NODA. Chelator p -NO2 -PhPr-NODA exhibited increased Al (III) complexation kinetics determined by AA III complexation kinetic studies and stronger coordination ability towards [AlF] 2+ according to DFT calculation studies in comparison with hexadentate chelator NOTA. As a proof of concept, bifunctional chelator p -SCN-PhPr-NODA was furthermore conjugated to a PSMA targeting moiety Glu-urea-Lys to form NODA-PrPh-GuL. The conjugated peptide showed acceptable radiochemical yield (12.5–16.4%) and efficiency with an excellent radiochemical purity (∼100% after SPE purification) in Al 18 F labeling. The labeled peptide exhibited good in vitro stability and significant specificity for PSMA. Biodistribution study and MicroPET scan in healthy Kun Ming mice with the labeled peptide were performed and demonstrated excellent in vivo stability of Al 18 F-labeled construct. In general, the successful application of the new bifunctional chelator in labeling dipeptide Glu-urea-Lys with Al 18 F could facilitate its possibility in conjugating with other peptides for PET imaging with enhanced in vivo stability, thus providing better in vivo performances.