Translation of smart contrast agents for brain tumor characterization by MR

描述(由申请人提供)：癌症研究需要非侵入性的pH和温度测绘，因为这些参数被用于肿瘤诊断或治疗。为了达到这一目标，由顺磁性稀土离子(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(SCA)已经被开发出来。我们已经证明了两种商用的基于Tm3+的SCA，TmDOTP5和TmDOTMA，提供了细胞外pH/温度图，并提供了对移位冗余偏差的生物传感器成像(BIREDS)。这些类型的SCA被用作MRS移动剂，以分离内源分子(或离子)的共振。然而，鸟牌映射了来自SCA本身的不可交换质子(即CHX)的1H信号，这与以可交换质子(例如OH或NHX)为特征的顺磁化学交换饱和转移(PARACEST)试剂形成了对比。鸟类对不可交换质子的检测提供了提取温度/pH的冗余性，化学位移成像(CSI)数据可以快速获取，具有良好的信噪比(SNR)，并且量化几乎不受磁场强度(Bo)、较差的Bo垫片条件和SCA浓度的影响。在11.7T的高速2D CSI中，TmDOTP5-(磷酸，高电荷)和TmDOTMA-(羧酸，低电荷)分别使大鼠大脑皮层的空间分辨率达到~10；lt；L或更高。在TmDOTMA中存在-CH3部分-使SNR提高约5W。耶鲁大学和大循环公司的合作伙伴关系将研究四种新型的基于Ln3+的环化合物。然而，为了以~1&lt；L的空间分辨率(在microPET和microSPECT的范围内)绘制跨越大鼠大脑皮质到皮质下区域的肿瘤图，我们将首先通过将相控阵射频技术与球面编码的k空间3D CSI相结合来实现全脑覆盖(目标1)。我们将合成对pH和/或温度具有更高灵敏度/特异度的独特的SCA(目标2)。这些新的SCA(即，磷酸酯和丙氨酸酰胺及其19F标记的类似物)将具有高信噪比、具有两个CH3部分的不可交换质子、通过排除膦酸而有利的生物分布以及由于较低的SCA电荷而改善血脑屏障(BBB)的通透性。然后，每个SCA将由MR表征其对生理参数的敏感性(S)，并测试其动力学惰性和血脑屏障通透性(目标3)。然后我们将检查它们的毒性和生物分布(目标4)。最后，我们将应用这些SCA来研究大鼠脑内9L和CNS-1肿瘤(目标5)。在大鼠身上的拟议工作是临床前开发和移植到人类的门户，因为有明显的工业迹象表明，用鸟类或PARACEST试剂进行分子成像是可行的。拟议工作的最终产品将有助于确定最有可能的结构特征，并具有可接受的毒理学和生物分布。如果这种临床前开发是成功的，那么它将代表着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.