Development and Validation of Nerve-Targeted Bacteriochlorin Sensors

Wereport an innovative approach to producing bacteriochlorins(bacs) via formal cycloaddition by subjecting a porphyrin to a trimolecularreaction. Bacs are near-infrared probes with the intrinsic abilityto serve in multimodal imaging. However, despite their ability tofluoresce and chelate metal ions, existing bacs have thus offeredlimited ability to label biomolecules for target specificity or havelacked chemical purity, limiting their use in bio-imaging. In thiswork, bacs allowed a precise and controlled appending of clickablelinkers, lending the porphyrinoids substantially more chemical stability,clickability, and solubility, rendering them more suitable for preclinicalinvestigation. Our bac probes enable the targeted use of biomoleculesin fluorescence imaging and Cerenkov luminescence for guided intraoperativeimaging. Bacs' capacity for chelation provides opportunitiesfor use in non-invasive positron emission tomography/computed tomography.Herein, we report the labeling of bacs with Hs1a, a (NaV1.7)-sodium-channel-bindingpeptide derived from the Chinese tarantula Cyriopagopusschmidti to yield Bac-Hs1a and radiolabeled Hs1a,which shuttles our bac sensor(s) to mouse nerves. In vivo, the bacsensor allowed us to observe high signal-to-background ratios in thenerves of animals injected with fluorescent Bac-Hs1a and radiolabeledHs1a in all imaging modes. This study demonstrates that Bac-Hs1a and[Cu-64]Cu-Bac-Hs1a accumulate in peripheral nerves, providingcontrast and utility in the preclinical space. For the chemistry andbio-imaging fields, this study represents an exciting starting pointfor the modular manipulation of bacs, their development and use asprobes for diagnosis, and their deployment as formidable multiplexnerve-imaging agents for use in routine imaging experiments.

Automated summary

In this study, an innovative method was reported to produce bacteriochlorins (bacs) by subjecting a porphyrin to a trimolecular reaction. Bacs are near-infrared probes with the ability to serve in multimodal imaging. The study demonstrated the precise and controlled appending of clickable linkers to bacs, which greatly improved their chemical stability, clickability, and solubility, making them more suitable for preclinical investigation.