Molecular brain imaging with engineered vasoactive probes
Biochemistry
Final Report Abstract
Brain function depends on the dynamic interplay of a plethora of molecular processes which act on different spatial and temporal scales. Understanding healthy and pathological states of the brain thus requires investigating its molecular function with spatiotemporal precision. Still, timeresolved imaging of signaling molecules on a brain-wide scale in living organisms remains challenging and represents a major roadblock for unraveling key molecular brain processes. In this project, we developed a molecular brain imaging approach that addresses key shortcomings of current methods. It involves vasoprobes, imaging probes that cause local blood flow and oxygenation changes, detectable by various well-established hemodynamic imaging techniques, including preclinical magnetic resonance imaging (MRI). Vasoprobes can be imaged in vivo at nanomolar concentrations yielding over 1000-fold greater detectability compared to previously developed MRI probes, and approaching potency of nuclear probes, without using radioactive or metallic components. I designed vasoprobe-based molecular sensors called activatable vasoprobes for analyte targeting (AVATars) and engineered variants that detect target molecules such as the neurotransmitters dopamine and glutamate. AVATars permit in vivo imaging of molecular species at nanomolar concentrations characteristic for many signaling molecules, biomarkers, and therapeutic agents. The high potency and small size of AVATars enable their delivery into large regions of the brain via minimally invasive routes and pave the way towards fully noninvasive delivery which is critical for applications in primates and humans. Combined with the engineerable, protein-based probe design and detectability in multiple widely-used imaging modalities, AVATars represent a versatile in vivo approach for visualizing molecular signaling on a brain-wide scale.
Publications
- (2020) Target-responsive vasoactive probes for ultrasensitive molecular imaging. Nature Communications. 11, 2339
Ohlendorf R, Wisniowska A, Desai M, Barandov A, Slusarczyk AL, Li N, Jasanoff A
(See online at https://doi.org/10.1038/s41467-020-16118-7)
