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Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T1molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.

In this study, we designed and synthesized a highly stable manganese (Mn2+)-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd3+) chelates and evaluated its usage as a T1hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r1relaxivity (2.3 mM–1s–1) than clinically approved Mn2+-based hepatobiliary complex Mn-DPDP (1.6 mM–1s–1) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd3+-based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn2+chelate are comparable to those of Gd3+-based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.