Speaker: Sajal Sen, Ph.D. Affiliation: Simons Postdoctoral Fellow, Alan Jasanoff Laboratory, MIT
Talk title: Probing Cholinergic Brain Function Using Multimodal Molecular Imaging Abstract: Autism spectrum disorders (ASD) are a diverse family of neurodevelopmental conditions that lack any consistent biomarkers to date. Cholinesterase (ChE) enzymes, which lyse choline-based esters at cholinergic synapses, have been emerging as a potential therapeutic target in ASDs, and could serve as synapse-specific biomarkers for these disorders. However, probe technologies to correlate ChE activity and ASD are not yet available. Our ongoing research, therefore, seeks to design and validate novel ChE-sensitive MRI contrast agents to probe cholinergic phenotypes in ASD models, facilitate therapy development, and ultimately establish a non-invasive diagnostic tool for the clinical evaluation of autistic patients. Our imaging agent design is based on a previously validated molecular mechanism developed in the Jasanoff lab to detect brain enzyme activity in animal models. The new contrast agent uses a chemical framework that facilitates probing ChE activity via multimodal imaging including MRI and optical methods. This added feature will permit valuable integration of readouts obtained over a range of spatial scales, both in living subjects and postmortem tissue. In this colloquium, I will describe the synthesis and validation of pilot imaging probes in vitro, as well as initial in vivo results using a lead ChE-responsive compound. This work is thus yielding novel tools for autism research, with long-term potential for evaluating cholinergic function in human subjects.