Strained Cyclooctyne as a Molecular Platform for Construction of Multimodal Imaging Probes

Abstract

Small-molecule-based multimodal and multifunctional imaging probes play prominent roles in biomedical research and have high clinical translation ability. A novel multimodal imaging platform using base-catalyzed double addition of thiols to a strained internal alkyne such as bicyclo[6.1.0]nonyne has been established in this study, thus allowing highly selective assembly of various functional units in a protecting-group-free manner. Using this molecular platform, novel dual-modality (PET and NIRF) uPAR-targeted imaging probe: (64)Cu-CHS1 was prepared and evaluated in U87MG cells and tumor-bearing mice models. The excellent PET/NIRF imaging characteristics such as good tumor uptake (3.69%ID/g at 2 h post-injection), high tumor contrast, and specificity were achieved in the small-animal models. These attractive imaging properties make (64)Cu-CHS1 a promising probe for clinical use.

Dual-Modality Imaging of Prostate Cancer with a Fluorescent and Radiogallium-Labeled Gastrin-Releasing Peptide Receptor Antagonist

“…Thus, modification of HZ220 with different spacers may improve affinity. Recently, other novel strategies have been introduced to construct dual-modality scaffolds (12,13); it will also be interesting to investigate how these scaffolds influence the ligand affinity and in vivo pharmacologic behavior.…”

“…Among several strategies that have been used to design dualmodality probes for in vivo targeting (12)(13)(14), we proposed to use 2 amines of lysine for conjugating radionuclide-chelated complexation and near-infrared fluorescent (NIRF) dye, respectively. For this study, we designed and synthesized a new 68 Ga and fluorescentconjugated GRPr antagonist ( 68 Ga-HZ220) based on the affinity sequence of 68 Ga-DOTA-RM2 ( Fig.…”

Universal Molecular Scaffold for Facile Construction of Multivalent and Multimodal Imaging Probes

“…5–8 However, the preparation of small molecular probes remained a challenging task. Although considerable efforts have been made to simplify the synthesis of small-molecule-based multivalent/multimodal imaging probes, 9–15 synthetic procedures are still complicated. Moreover, the extensive protections–deprotections, multiple chromatographic purifications, and low yields of current strategies heavily hinder the wide application of such promising probes in preclinical and/or clinical studies.…”

“…The new designed BFC possesses a chelator and a linker simultaneously; thus, the number of synthetic steps was significantly reduced to avoid extensive protections/deprotections and/or multifunctional linker preparations. 9–11 In addition, unlike many current platforms suffering from the regio- and/or diastereoselectivity problem, 11–13,15 the introduced carboxylic acid and azido functional groups provided high regioselectivity. Moreover, metal-free click chemistry was applied in the last step in order to further simplify the preparation and maintain high yield.…”

“…Moreover, metal-free click chemistry was applied in the last step in order to further simplify the preparation and maintain high yield. 9–15 This metal-free click reaction is completed in nearly quantitative yield, and subsequently facilitates the ease of synthesis and simplifies the purification. Last but not least, unlike many other scaffolds designed only for certain types of substrates, 9,10 our BFC-based scaffold is a universal and robust platform that can be applied to prepare multivalent or multimodal imaging probes consisting of any interested ligand(s), dye(s), and other functional moieties.…”