Novel Chemistries For Activatable Molecular Imaging Probes Applicable To Magnetic Resonance Imaging And Positron Emission Tomography

酶和高反应性的天然小分子是细胞的主力，并通过明确的化学机制对生理产生影响。这些生物化学物质的活性在健康期间受到很好的调节，但在疾病过程中经常发生重大变化。通过测量这些生化工作者的活性，可以在任何外在体征或症状发生之前很早就检测到可能最终导致疾病发作或通过治疗逆转的亚细胞过程。分子成像是一个新兴的领域，特别关注这些亚细胞活动的成像，并且严重依赖于可以开发成像示踪剂的新化学。这些小分子示踪剂在成像之前被注射，并且被感兴趣的主力靶标作用以改变它们在疾病区域（例如在肿瘤中）中的行为。这导致示踪剂的化学变化，可以通过磁共振成像（MRI）或正电子发射断层扫描（PET）扫描无创检测。MRI和PET是有关疾病和治疗的基础研究以及临床医学的重要工具，提供非侵入性三维图像，其分辨率和灵敏度是其他成像方式无法比拟的。虽然MRI和PET分子成像有望增强研究和跟踪健康和疾病的方式，但由于缺乏可用于使用这些模式询问主力活动的示踪剂化学物质，因此尚未发挥其潜力。我的工作证明了一种新的分子成像策略的原理：设计小分子示踪剂，当一个特定的主力存在并活跃时，这些示踪剂可以在细胞和组织中自组装成大结构。拟议的研究计划将把这种自组装的分子成像策略付诸实践。将开发新的化学方法来设计包含示踪剂化学平台的大型自组装工具箱，该工具箱适用于MR和PET成像的广泛的主力目标。该研究计划还将重新评估目前用作MRI示踪剂的材料的安全性，因为人们担心它们必须掺入重金属原子。将制造缺乏这些有毒重金属的材料，但仍然可以产生MRI的成像对比度。有了这些用于示踪剂设计的新化学工具，询问重要的生物化学主力的活性的能力将对研究疾病和创新治疗的基本过程产生实质性的短期影响，并对加拿大的临床分子成像和疾病管理产生潜在的长期影响。

Enzymes and highly reactive, naturally occurring small molecules are the workhorses of the cell, and exert their effects on physiology through well-defined chemical mechanisms. The activity of these biochemical species is well regulated during health, but often changes substantially during disease processes. By measuring the activity of these biochemical workhorses, the subcellular processes that may ultimately result in the onset of disease, or its reversal through treatment efforts, can be detected very early on before any outward signs or symptoms occur. Molecular imaging is an emerging field that is specifically concerned with imaging these sorts of subcellular activities, and is heavily reliant on novel chemistries through which imaging tracers can be developed. These small molecule tracers are injected prior to imaging, and are acted upon by the workhorse target of interest to change their behavior in the area of disease, for example in a tumor. This results in a chemical change to the tracer that can be detected non-invasively through magnetic resonance imaging (MRI) or positron emission tomography (PET) scans. MRI and PET are important tools for fundamental research regarding disease and treatment, as well as clinical medicine, offering non-invasive, three-dimensional images with resolution and sensitivity unmatched by other imaging modalities. While MRI and PET molecular imaging holds promise to enhance the way health and disease can be studied and tracked, it has not yet reached its potential due to a lack of tracer chemistry available to interrogate workhorse activities using these modalities. My work has proved the principle of a new molecular imaging strategy: designing small molecule tracers that self-assemble into large structures in cells and tissues when a particular workhorse is present and active. The proposed research program will move this molecular imaging strategy of self-assembly into practice. New chemical approaches will be developed to design a large self-assembly toolbox containing tracer chemistry platforms applicable to a broad range of workhorse targets for both MR and PET imaging. The research program will also reevaluate the safety of materials currently used as MRI tracers, since there have been concerns regarding their necessary incorporation of heavy metal atoms. Materials will be made that lack these toxic heavy metals but that can still produce imaging contrast for MRI. With these new chemical tools for tracer design, the capacity to interrogate the activity of important biochemical workhorses would have substantial short term impact on studying fundamental processes in disease and innovative treatments, and a potential for long term impact on clinical molecular imaging in Canada and the management of disease.