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.

Keywords: alkynes; fluorescence; imaging agents; strained molecules; thiols.

Figure 1.

A) The PET/CT images of U87MG-tumor-bearing mice (red rings indicate the location of the tumor, n = 4 per group) acquired at 1, 2, 4, and 24 h after tail vein injection of ⁶⁴Cu-CHS1 with and without the blocking agent AE105. B) The fluorescence images of U87MG tumors at 1, 2, and 4h after tail vein injection of ⁶⁴Cu-CHS1 with and without the blocking agent AE105. C) PET imaging, represented as the tumor-to-normal tissue (T/N) ratio for ⁶⁴Cu-CHS1 at 1, 2, 4, and 24 h. D) NIRF imaging, represented as (T/N) ratio for the ⁶⁴Cu-CHS1 probe (black bar) and blocking group (red bar) at 1, 2, and 4 h.

Scheme 1.

A new strategy for the construction of multimodal imaging probes. a) The photocatalyzed thiol–yne reaction. b) Approach discussed in the present work.