New Dopamine Transporter MRI Nanoprobes for Addiction Research

描述(申请人提供)：甲基苯丙胺(冰毒)滥用和依赖是美国和国外的主要心理健康和执法问题。PET研究一致地表明，甲基苯丙胺成瘾者纹状体中的多巴胺转运体(DAT)密度慢性降低。这是一类特殊的多巴胺受体，主要定位于纹状体、伏隔核和黑质，并作为治疗药物的重要靶点与药物滥用有关。PET扫描通过使用针对某些类别的多巴胺受体的选择性探针，促进了总体上在冰毒成瘾和药物滥用研究方面的重大进展--这一方法受到PET扫描分辨率相对较低的限制，而且拥有PET设施的机构也相对较少。这项应用的目标是开发非放射性生物纳米颗粒，可用于使用常规MRI扫描仪进行基于受体的成像成瘾研究，这种扫描仪可在更多的设施中使用，并且提供比PET更好的解剖分辨率。将设计两部分纳米探测器(&lt；100纳米)。一部分是含有磁共振造影剂的分子笼状载体。这种载体将由笼状蛋白构成，这是一种人体用来在细胞内运输物质的自然产生的蛋白质。第二组分将是与DAT高亲和力和高特异性结合的分子。该组分将附着在包覆载体的聚乙二醇分子上。一系列研究将确定这些纳米探针在体内和体外的亲和力和特异性。这种MRI工具检测DAT变化的可行性将在未来对接触冰毒的动物和人类的成像研究中得到证明。这种非放射性纳米探针可以重复使用，以监测疾病的进展和康复过程。长期监测对慢性冰毒使用者尤其重要。如果这项研究项目成功，它将为分子脑成像提供工具和技术，理论上可以比PET具有更高的分辨率。高分辨率稳定分子纳米探针的发展将为成瘾和药物滥用中受体和转运体异常的研究提供重要的新的研究工具。这种新的纳米技术可能作为一种提高诊断能力的试剂具有实用价值，并可能作为一种专门针对相关大脑系统的药物输送系统。公共卫生相关性：高分辨率稳定的MRI分子纳米探针的开发将为成瘾和药物滥用中转运蛋白异常的研究提供一个重要的新的研究工具。这种新的纳米技术可能作为一种提高诊断能力的试剂具有实用价值，并可能作为一种专门针对相关大脑系统的药物输送系统。

DESCRIPTION (provided by applicant): 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.