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

酶和高活性的，自然产生的小分子是细胞的主力，并通过明确的化学机制发挥其生理作用。这些生物化学物种的活性在健康期间受到良好调节，但在疾病过程中往往发生实质性变化。通过测量这些生化大马的活性，亚细胞过程可能最终导致疾病的发作，或通过治疗努力逆转疾病，可以在任何外在体征或症状出现之前很早就被发现。分子成像是一个新兴的领域，它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型化学物质。这些小分子示踪剂在成像之前被注射，并被感兴趣的主要目标作用，以改变它们在疾病区域（例如肿瘤）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）扫描非侵入性地检测到。MRI和PET是疾病和治疗以及临床医学基础研究的重要工具，提供无创的三维图像，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分子成像有望增强健康和疾病的研究和追踪方式，但由于缺乏可用的示踪化学来使用这些模式来询问主力活动，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。提出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一个大型的自组装工具箱，其中包含适用于MR和PET成像的各种主要目标的示踪化学平台。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，因为人们担心它们可能会掺入重金属原子。人们将制造出不含这些有毒重金属的材料，但仍能产生MRI成像造影剂。有了这些用于示踪剂设计的新化学工具，询问重要生物化学主力活性的能力将对研究疾病的基本过程和创新治疗产生重大的短期影响，并可能对加拿大的临床分子成像和疾病管理产生长期影响。

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.