Multivalent PARACEST agents for quantitative molecular imaging

用于定量分子成像的多价 PARACEST 试剂

• 批准号: 7934868
• 负责人: Dewan Syed Fahmeed Hyder
• 金额: $ 35.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934868
• 关键词: Acetamides; Affect; Attributes of Chemicals; Binding; Biomedical Research; Biosensor; Brain; Calibration; Characteristics; Charge; Chemicals; Clinical; Clinical Research; Complex; Contrast Media; Detection; Diagnostic; Disease; Environment; Extracellular Space; Future; Generations; Glucose; Goals; Health; Human; Image; Ions; Lanthanoid Series Elements; Ligands; Magnetic Resonance Imaging; Measurement; Measures; Methods; Molecular Weight; New Agents; Physiologic pulse; Property; Protons; Quantitative Evaluations; Rattus; Relaxation; Sensitivity and Specificity; Signal Transduction; Specificity; Techniques; Temperature; Time; Variant; Water; arm; base; bioimaging; cyclen; design; extracellular; improved; in vivo; interstitial; lipophilicity; molecular imaging; public health relevance; radiofrequency; sugar; technology development; tool

DESCRIPTION (provided by applicant): MRI contrast agents that affect water proton relaxation lack sensitivity or specificity for molecular imaging of disease. Specific extracellular targets (e.g., ions, metabolites) can be imaged with MRI probes which have exchangeable protons. The chemical exchange saturation transfer (CEST) technique detects exchange between bulk water protons and -NHx or -OH protons in diamagnetic molecules or protons of an inner sphere of bound water that is shifted by the paramagnetic core of a lanthanide III (Ln3+) ion. Although paramagnetic CEST or PARACEST agents - especially derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA4-) - have great translational potential, quantitative molecular imaging is limited by contributions to the CEST effect from unmeasured influences of the agent's concentration and local environment (i.e., temperature and pH). We propose a new class of DOTA ligands containing Ln3+ that will allow measurement of these parameters while still retaining the CEST effect for an extracellular target. It is well known that paramagnetic complexes of 1,4,7,10-tetraazacyclododecane, primarily used as MRS shift agents, have several non- exchangeable protons that are easily detectable for agent concentration assessment and furthermore these signals are very sensitive to temperature and pH. Thus biosensor imaging of redundant deviation in shifts (BIRDS) of non-exchangeable protons (in <L voxels) can provide absolute measurements of temperature, pH, and agent concentration in the interstitial space of rat brain. To improve CEST quantification of DOTA- tetraamides, which are good PARACEST agents and biologically favored, we will incorporate properties of BIRDS into them. The new class of DOTA-tetraamides will contain both non-exchangeable and exchangeable protons (i.e., BIRDS and CEST properties) in the same probe. By exploiting C2 symmetry, one pair of ligating arms will feature BIRDS for quantitative evaluation of temperature, pH, and agent concentration, whereas another pair of ligating arms will attribute CEST for assessing the variations of an ion or a metabolite in the extracellular milieu. First, we will synthesize and characterize variants of DOTA-tetraamides which contain several non-exchangeable protons, in the form of -CH3 moieties, to enhance BIRDS properties. The -CH3 moieties surrounding the Ln3+ are designed for high BIRDS sensitivity to allow ~1 <L voxels in vivo - which is comparable to microSPECT and microPET methods - while at the same time provide sufficient chemical shift redundancy for simultaneous temperature and pH determination. Next, we will add Zn2+-, Ca2+-, and glucose- specific CEST characteristics onto prototypical multivalent DOTA-tetraamides. CEST properties will depend on each agent possessing a very large chemical shift separation between bound and bulk water and bound water lifetime of the appropriate range such that saturation transfer can enhance the CEST effect. Finally, we will conduct in vivo rat brain studies with some of the new multivalent agents that are most kinetically stable, possess low overall charge, and/or have low molecular weight. Since all new agents will be built on the DOTA framework, we expect some of them to have translational prospects. PUBLIC HEALTH RELEVANCE: Molecular imaging of extracellular targets with MRI is possible by detecting water-exchangeable protons in paramagnetic macrocyclics with chemical exchange saturation transfer (CEST). However CEST is limited by unknown influences of the agent's concentration and local environment (i.e., temperature and pH). Since MRS shift agents contain non-exchangeable protons for appraisal of these unmeasured parameters with biosensor imaging of redundant deviation in shifts (BIRDS), the new class of multivalent paramagnetic agents will contain both BIRDS and CEST properties for quantitative molecular imaging.

描述（由申请人提供）：影响水质子弛豫的MRI造影剂缺乏疾病分子成像的敏感性或特异性。特定的细胞外目标（例如离子、代谢物）可以使用具有可交换质子的 MRI 探针进行成像。化学交换饱和转移 (CEST) 技术可检测大量水质子与反磁性分子中的 -NHx 或 -OH 质子或结合水内球质子之间的交换，这些质子被镧系 III (Ln3+) 离子的顺磁性核心移动。尽管顺磁性 CEST 或 PARACEST 试剂 - 特别是 1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸酯 (DOTA4-) 的衍生物 - 具有巨大的转化潜力，但定量分子成像受到对 CEST 效应的贡献的限制免受药剂浓度和当地环境（即温度和 pH 值）不可测量的影响。我们提出了一类包含 Ln3+ 的新型 DOTA 配体，它将允许测量这些参数，同时仍然保留细胞外靶标的 CEST 效应。众所周知，1,4,7,10-四氮杂环十二烷的顺磁性复合物主要用作 MRS 位移剂，具有多个不可交换的质子，可以轻松检测到这些质子以评估试剂浓度，而且这些信号对温度和 pH 值非常敏感。因此，不可交换质子（<L 体素）的位移冗余偏差 (BIRDS) 的生物传感器成像可以提供大鼠脑间隙中温度、pH 和药剂浓度的绝对测量。为了提高 DOTA-四酰胺（DOTA-四酰胺是良好的 PARACEST 制剂且具有生物学优势）的 CEST 定量，我们将把 BIRDS 的特性纳入其中。新型 DOTA-四酰胺将在同一探针中同时包含不可交换和可交换质子（即 BIRDS 和 CEST 特性）。通过利用 C2 对称性，一对连接臂将具有 BIRDS，用于定量评估温度、pH 和试剂浓度，而另一对连接臂将具有 CEST，用于评估细胞外环境中离子或代谢物的变化。首先，我们将合成并表征 DOTA-四酰胺的变体，其包含多个不可交换质子（以 -CH3 部分的形式），以增强 BIRDS 特性。 Ln3+ 周围的 -CH3 部分专为实现高 BIRDS 灵敏度而设计，可实现 ~1 <L 体内体素（与 microSPECT 和 microPET 方法相当），同时为同时测定温度和 pH 提供足够的化学位移冗余。接下来，我们将在原型多价 DOTA-四酰胺上添加 Zn2+-、Ca2+- 和葡萄糖特异性 CEST 特征。 CEST 特性将取决于每种试剂在结合水和本体水之间具有非常大的化学位移分离以及适当范围的结合水寿命，使得饱和转移可以增强 CEST 效果。最后，我们将使用一些动力学最稳定、总电荷较低和/或分子量较低的新型多价药物进行体内大鼠脑研究。由于所有新代理都将构建在 DOTA 框架上，我们预计其中一些具有转化前景。 公共健康相关性：通过化学交换饱和转移 (CEST) 检测顺磁大环化合物中的水可交换质子，可以使用 MRI 对细胞外靶标进行分子成像。然而，CEST 受到试剂浓度和当地环境（即温度和 pH 值）的未知影响的限制。由于 MRS 位移剂含有不可交换的质子，可通过位移冗余偏差生物传感器成像 (BIRDS) 来评估这些未测量的参数，因此新型多价顺磁剂将包含用于定量分子成像的 BIRDS 和 CEST 特性。