In vivo detection of hydrogen sulfide in the brain of live mouse: application in neuroinflammation models.

Purpose: Hydrogen sulfide (HS) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain HS in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous HS in the brain of live mice.

Methods: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for HS. The same ATSM-FITC ligand was quantitatively labeled with [Cu]CuCl to obtain a radioactive [Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models.

Results: The Cu(ATSM-FITC) complex reacts instantly with HS to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to HS. Endogenous HS levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain HS concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased HS levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging.

Conclusion: Our biosensor can be readily utilized to study brain HS function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.