Toward Functional Molecular Neuroimaging Using Vasoactive Probes in Human Subjects

The establishment of new and precise strategies for mapping brain activity in human subjects is one of the highest priorities of the BRAIN Initiative. Here we propose to meet this challenge by developing a transformative noninvasive molecular neuroimaging approach capable of mapping molecular events in the brain; the method will offer a combination of sensitivity and resolution that could ultimately revolutionize neuroscientific investigation of human subjects. Our strategy is based on a fundamentally new type of chemical imaging probe designed to produce noninvasive neuroimaging readouts by purposefully manipulating endogenous hemodynamic contrast in the brain-in effect hijacking the blood oxygen level dependent (BOLD) effect to perform neural target-specific molecular imaging. This unprecedented concept combines three key advantages: First, by providing time-dependent sensitivity to molecular species such as neurotransmitters, our strategy will enable well-defined neurobiological phenomena to be mapped dynamically across the brain, dramatically surpassing today's functional imaging approaches. Second, by influencing an endogenous contrast source detectable by virtually any noninvasive imaging modality, the new approach will be compatible with a formidable existing infrastructure for experimentation and analysis over multiple spatial and temporal scales and applicable in the lab, field, or clinic. Third, by circumventing limitations of established optical, magnetic, and radioactive probe designs, the new vasoactive imaging probes will combine exquisite sensitivity approaching that of positron emission tomography (PET) with spatiotemporal resolution comparable to functional magnetic resonance imaging (fMRI), while at the same time avoiding toxicity associated with existing imaging agents. The sensitivity afforded by vasoactive probes will also permit minimal doses of these agents to be delivered noninvasively past the blood-brain barrier (BBB), an essential requirement for human functional molecular neuroimaging.

In the spirit of this "planning" grant, we will complete three Specific Aims that set the stage for next- generation functional neuroimaging in humans. In Aim 1 we will build on our preliminary work with vasoactive imaging probes to create new sensors for detecting the neurotransmitters dopamine and glutamate in the brain. In Aim 2, we will modify vasoactive probes to enable noninvasive trans-BBB delivery by means of receptor mediated transcytosis. In Aim 3, we will adapt our vasoactive probes for neuroimaging experiments in primates-a key stepping stone toward imaging trials in people. To these Aims, we bring a collaborative research team with unparalleled expertise in a combination of molecular engineering and imaging, fMRI in rodents and nonhuman primates, and human functional brain imaging. This strength in all aspects of our research trajectory will optimize our ability within eight years to validate the new technology in human subjects, where we expect it to become a powerful approach for functional imaging in both scientific and medical contexts.