Chemiluminescence is the light production directly from a highly exothermic chemical reaction by generating electronically excited species, and the light will be generated upon relaxation to the ground state. We utilize this light as the readout to construct imaging agents for reactive species. Chemiluminescence as an imaging modality has many advantages compared with current widely used imaging modalities, such as fluorescence and bioluminescence. The main advantages are the elimination of extraneous light excitation or genetic modification, which are required for fluorescence and bioluminescence imaging. Therefore, chemiluminescence as a imaging modality holds great potential for in vivo imaging.
In this dissertation, based on different reactive species, several reaction-based imaging agents have been designed, synthesized, characterized and applied for cellular and in vivo studies. Structural modifications have been conducted to obtain better imaging agents. For example, the introduction of ortho-chloro substitution to the reactive handle lowers the pKa of the chemiluminescent scaffold, and the introduction of electron withdrawing groups at the para position helps to increase chemiluminescence emission. CHS-3, HyCL-2, and PNCL are chemiluminescent probes for hydrogen sulfide (H2S), peroxynitrite (ONOO–) and hypoxia and tissue oxygenation. All of them demonstrate high sensitivity and selectivity towards the analyte of interest. CHS-3 is the first reaction-based chemiluminescent probe demonstrating that chemiluminescence can be used as an imaging modality for in vivo imaging in wild-type animals. HyCL-2 with the hypoxia responsive para-nitrobenzyl alcohol functionality, has the ability to differentiate different tissue oxygenation and image tumor hypoxia. PNCL is an enhancer free chemiluminescent probe that features a ortho- acrylonitrile group to the isatin for enhanced luminescence emission and an isatin functionality as a ONOO– specific handle. PNCL has been applied for the detection of endogenously generated ONOO– in RAW 264.7 macrophages. Finally, we are expanding upon the HyCL probe series with green and near-infrared emitting modifications. These chemiluminescent scaffolds are in the process of characterization.
Alexander R. Lippert
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Cao, Jian, "Chemiluminescent Agents for In Vivo Imaging" (2018). Chemistry Theses and Dissertations. 4.