Hybrid Multimodal Imaging Synthons for Chemoselective and Efficient Biomolecule Modification with Chelator and Near-Infrared Fluorescent Cyanine Dye

Ralph Hübner; Valeska von Kiedrowski; Vanessa Benkert; Björn Wängler; Ralf Schirrmacher; Roland Krämer; Carmen Wängler

doi:10.3390/ph13090250

Hybrid Multimodal Imaging Synthons for Chemoselective and Efficient Biomolecule Modification with Chelator and Near-Infrared Fluorescent Cyanine Dye

Pharmaceuticals (Basel). 2020 Sep 16;13(9):250. doi: 10.3390/ph13090250.

Authors

Ralph Hübner¹, Valeska von Kiedrowski², Vanessa Benkert³, Björn Wängler², Ralf Schirrmacher⁴, Roland Krämer³, Carmen Wängler¹

Affiliations

¹ Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
² Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
³ Institute of Inorganic Chemistry, Heidelberg University, Im Neuenheimer Feld 274, 69120 Heidelberg, Germany.
⁴ Department of Oncology, Division of Oncological Imaging, University of Alberta, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada.

Abstract

The development of hybrid multimodal imaging synthons (MIS), carrying in addition to a chelator for radiometal labeling also a near-infrared (NIR) fluorescent cyanine dye was the aim of this work. The MIS should be introducible into biomolecules of choice via an efficient and chemoselective click chemistry reaction. After chemical optimization, a successful synthetic strategy towards such hybrid MIS was developed, based on solid phase-based synthesis techniques and applying different near-infrared fluorescent cyanine dyes. The developed hybrid agents were shown to be easily introducible into a model homobivalent peptidic gastrin-releasing peptide receptor- (GRPR)-specific carrier without forming any side products and the MIS as well as their bioconjugates were radiolabeled with the positron-emitter ⁶⁸Ga³⁺. The hybrid multimodal agents were characterized with regard to their log_Ds, GRPR target affinities and photophysical characteristics. It could be shown that the properties of the bioconjugates were not per se affected by the introduction of the MIS but that the cyanine dye used and specifically the number of comprised negative charges per dye molecule can have a considerable influence on target receptor binding. Thus, the molecular toolbox described here enables the synthesis of tailored hybrid multimodal imaging synthons for biomolecule modification, meeting the specific need and envisioned application of the combined imaging agent.

Keywords: 68Ga3+; GRPR affinity; NIR fluorescent dye; chelator; click chemistry; cyanine dye; multimodal imaging; peptide carrier; peptide homodimer.