Multivalent PARACEST agents for quantitative molecular imaging

用于定量分子成像的多价 PARACEST 试剂

• 批准号: 8470166
• 负责人: Dewan Syed Fahmeed Hyder
• 金额: $ 30.06万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470166
• 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.

描述（由申请人提供）：影响水质子弛豫的MRI对比剂缺乏对疾病分子成像的敏感性或特异性。可以使用具有可交换质子的MRI探针成像特定的细胞外靶（例如离子，代谢产物）。化学交换饱和转移（CEST）技术检测了散热性水质子与-NHX或-OH质子之间的交换，或者在结合水的内部球体的质子或质子中，这些质子被灯笼III（LN3+）离子的顺磁核转移。 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).我们提出了一类包含LN3+的DOTA配体，该配体将允许测量这些参数，同时仍保留细胞外靶标的CEST效应。众所周知，1,4,7,10-tetraazacyclododecane（主要用作MRS Shift剂）具有几种不可交换的质子，这些质子易于检测到代理浓度评估，并且这些信号对温度和pH非常敏感。因此，非交换质子（<l voxels）的冗余偏差（鸟类）的冗余偏差的生物传感器成像可以在大鼠脑的间隙空间中对温度，pH值和试剂浓度的绝对测量。为了改善对dotraamides的CEST定量，这是最有偏的药物，并且受到生物学上的青睐，我们将将鸟类的特性纳入其中。新的Dota-tetraamides将在同一探针中包含不可交换和可兑换的质子（即鸟类和CEST性质）。通过利用C2对称性，一对绑扎臂将以鸟类为特征，用于定量评估温度，pH值和剂浓度，而另一对绑扎臂将归因于评估离子或代谢物在细胞外环境中的变化。首先，我们将合成并表征dota-tetraamides的变体，这些变体包含以-CH3部分形式的几个不可交换的质子，以增强鸟类性质。 LN3+周围的-CH3部分是为高鸟类敏感性而设计的，可以在体内允许〜1 <L素 - 与微光谱和微晶体方法相当 - 而同时为同时温度和pH测定提供了足够的化学移位冗余。接下来，我们将在原型的多价dota-tetraamides中添加Zn2+ - ，Ca2+ - 和葡萄糖特异性CEST特性。 CEST性质将​​取决于每个药物在结合水和大块水之间具有非常大的化学位移分离，以及适当范围的水寿命，从而使饱和转移可以增强CEST效应。最后，我们将使用一些最稳定，总电荷和/或具有低分子量的新的多价药物进行体内大鼠脑研究。由于所有新代理商都将建立在DOTA框架上，因此我们希望其中一些具有翻译前景。