Methamphetamine (METH) abuse and dependence represent major mental health and law enforcement problems in the US and abroad. PET studies consistently showed chronic reduction in dopamine transporter (DAT) density in the striatum of methamphetamine addicts. This is a special class of dopamine receptors that are primarily localized in striatum, nucleus accumbens and substantia nigra, and have been implicated in drug abuse as important targets for therapeutic drugs. PET scans have facilitated major advances in studies of METH addiction and drug abuse in general, by using probes selective for certain classes of dopamine receptors--An approach limited by relatively low resolution of PET scans and also relatively few institutions have PET facilities. This application's goal is to develop non-radioactive bio-nanoparticles that can be used in addiction research for receptor based imaging with conventional MRI scanners, which are available in many more facilities, and which provide better anatomical resolution than PET. Two-part nanoprobes (<100 nanometers) will be designed. One part is a molecular cage carrier containing an MRI contrast agent. This carrier will be constructed out of clathrin, a naturally occurring protein the body uses for transporting materials inside cells. The second component will be a molecule that binds with high affinity and high specificity to DAT. This component will be attached to polyethylene glycol molecules coating the carrier. A series of studies will ascertain the affinity and specificity of these nanoprobes in vivo and in vitro. The feasibility of this MRI tool to detect DAT changes will be demonstrated in future imaging studies of animals and humans exposed to METH. This non-radioactive nanoprobe may be used repeatedly to monitor progression of the disease and recovery process. Long-term monitoring is especially important for chronic METH users. If this research project were successful it would provide tools and techniques for molecular brain imaging that theoretically could have higher resolution than PET. The development of high-resolution stable molecular nanoprobes will provide a major new research tool for research of receptor and transporter abnormalities in addiction and drug abuse. This new nanotechnology may have utility as an agent to enhance diagnosis, and may serve as a drug-delivery system that can specifically target relevant brain systems. PUBLIC HEALTH RELEVANCE: The development of high-resolution stable MRI molecular nanoprobes will provide a major new research tool for research of transporter abnormalities in addiction and drug abuse. This new nanotechnology may have utility as an agent to enhance diagnosis, and may serve as a drug-delivery system that can specifically target relevant brain systems.