Translation of smart contrast agents for brain tumor characterization by MR

描述（由申请人提供）：非侵入性pH和温度测绘是癌症研究所需要的，因为这些参数在肿瘤诊断或治疗中被利用。为了实现这一目标，由顺磁性镧系离子（Ln3+）和1,4,7,10四氮杂环十二烷（cyclen）衍生物组成的智能造影剂（SCAs）已经被开发用于mr。我们已经证明，两种基于Tm3+的商用SCAs TmDOTP5和TmDOTMA可以提供细胞外pH/温度图，并具有冗余偏移偏移（BIRDS）的生物传感器成像。这些类型的sca被用作MRS移位剂来分离内源性分子（或离子）的共振。然而，BIRDS绘制了来自SCA本身的不可交换质子（即CHx）的1H信号，这与具有可交换质子（例如OH或NHx）的顺磁化学交换饱和转移（PARACEST）剂形成对比。BIRDS对非交换质子的检测为提取温度/pH值提供了冗余，化学位移成像（CSI）数据的快速获取具有优越的信噪比（SNR），并且量化对磁场强度（Bo），薄层条件差和SCA浓度几乎不敏感。在11.7T下，高速二维CSI在大鼠大脑皮层中分别具有TmDOTP5-（磷酸，高电荷）和TmDOTMA-（羧酸，低电荷），可以实现~10 <L或更好的空间分辨率。TmDOTMA-中- ch3片段的存在使信噪比提高了约5W。耶鲁大学与macrocyclics公司的合作将研究四种新型的Ln3+环基配合物。然而，为了以~1 <L的空间分辨率（在microPET和microSPECT的限制范围内）绘制从大鼠大脑皮层到皮层下区域的肿瘤，我们将首先通过相控阵射频技术与球编码k空间3D CSI相结合实现全脑覆盖（Aim 1）。我们将合成对pH和/或温度具有更高敏感性/特异性的独特SCAs（目标2）。这些新的SCA（即膦酸酯和丙氨酸酰胺以及它们的19f标记的类似物）将具有具有两个-CH3基团的高信信比不可交换质子，通过排除膦酸而有利的生物分布，并且由于较低的SCA电荷而改善了血脑屏障（BBB）的通透性。然后，每个SCA将通过MR表征其对生理参数的敏感性，测试其动力学惰性和血脑屏障通透性（Aim 3）。然后我们将检查它们的毒性和生物分布（Aim 4）。最后，我们将把这些SCAs应用于大鼠脑9L和CNS-1肿瘤的研究（Aim 5）。拟议的大鼠研究是临床前开发的门户，并且即将转化为人类，因为用BIRDS或PARACEST药物进行分子成像有明确的工业迹象。拟议工作的最终产品将有助于确定具有可接受的毒理学和生物分布的最可能的结构特征。如果这种类型的临床前开发成功，那么它将代表诊断人类成像的巨大范例。

DESCRIPTION (provided by applicant): Non-invasive pH and temperature mapping is needed for cancer research because these parameters are exploited in tumor diagnosis or therapy. To that goal, smart contrast agents (SCAs) composed of paramagnetic lanthanide ion (Ln3+) with derivatives of 1,4,7,10 tetraazacyclododecane (cyclen) have been developed for MR. We have shown that two commercial Tm3+-based SCAs, TmDOTP5 and TmDOTMA, provide extracellular pH/temperature maps with biosensor imaging of redundant deviation in shifts (BIRDS). These types of SCAs are used as MRS shift agents to separate resonances of endogenous molecules (or ions). However BIRDS maps the 1H signals from non-exchangeable protons (i.e., CHx) of the SCA itself, which is in contrast to the paramagnetic chemical exchange saturation transfer (PARACEST) agent that features exchangeable protons (e.g., OH or NHx). Detection of the non-exchangeable protons by BIRDS provides redundancy to extract temperature/pH, the chemical shift imaging (CSI) data are acquired rapidly for superior signal-to-noise ratio (SNR), and quantification is nearly insensitive to the magnetic field strength (Bo), poor Bo shim conditions, and the SCA's concentration. BIRDS with high speed 2D CSI at 11.7T allows spatial resolution of ~10 <L or better in rat's cerebral cortex with TmDOTP5- (phosphonic acid, high charge) and TmDOTMA- (carboxylic acid, low charge), respectively. Presence of a -CH3 moiety in TmDOTMA- enables about 5W higher SNR. This Yale-Macrocyclics partnership will study four novel Ln3+ cyclen-based complexes. However to map tumors spanning from cortical to subcortical regions in rat brain with ~1 <L spatial resolution - which is within limits of microPET and microSPECT we will first achieve whole brain coverage by combining phased array radio frequency technology with spherically encoded k-space 3D CSI (Aim 1). We will synthesize unique SCAs with improved sensitivity/specificity for pH and/or temperature (Aim 2). These new SCAs (i.e., phosphonate ester and alanine-amide as well as their 19F-labelled analogs) will feature high SNR non-exchangeable protons with two -CH3 moieties, favorable biodistribution by exclusion of phosphonic acids, and improved permeability across the blood-brain barrier (BBB) because of lower SCA charge. Each SCA will then be characterized by MR for its sensitivity to physiological parameter(s), tested for its kinetic inertness, and BBB permeability (Aim 3). Then we will examine their toxicity and biodistribution (Aim 4). Finally we will apply these SCAs to study 9L and CNS-1 tumors in rat brain (Aim 5). The proposed work in rats are the gateway to pre-clinical development and translation to humans is on the horizon because there are clear industrial signs for molecular imaging with BIRDS or PARACEST agents. The final product of the proposed work would help identify the most probable structural features with acceptable toxicology and biodistribution. If this type of pre-clinical development is successful, then it would represent huge paradigms in diagnostic human imaging.