A Sensitive Zinc-Activated 129Xe MRI Probe
A Sensitive Zinc-Activated 129Xe MRI Probe
复制标题
DOI：
10.1002/anie.201109194
复制
发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Rousseau, Bernard
中科院分区：
文献类型：
--
作者：
Kotera, Naoko;Tassali, Nawal;Rousseau, Bernard
The divalent zinc cation, Zn2+, is an indispensable and ubiquitous element of the body.[1] As the second most abundant transition-metal ion in mammalian tissues, it is involved in many physiological and pathological processes. Zinc plays a vital role not only when bound to metalloproteins, but also in the form of mobile pools. A slight excess or lack of zinc ions can be connected to serious human afflictions, including heart disease, diabetes, cancer, and neurodegeneration such as Alzheimer s disease.[2] Today, only two noninvasive techniques, optical imaging and magnetic resonance imaging (MRI), have the potential to offer real-time monitoring of the Zn2+ distribution in different tissues of the body. However, optical methods suffer from limited penetration depth, which makes them unsuitable for global analysis of relatively large and opaque specimens, such as live animals.[3] On the other hand, MRI is a particularly powerful modality used clinically for anatomic imaging and provides three-dimensional images with excellent resolution. However, conventional molecular MRI techniques that rely on the observation of water protons and require the introduction of contrast agents still suffer from reduced sensitivity and often lack selectivity.[4] A few studies based on gadolinium complexes have been reported for Zn2+ imaging.[5] Nevertheless, to our knowledge, the detection threshold of free Zn2+ ions is 30 μm, a value slightly above the total Zn2+ concentration of 20 μm in blood. Therefore, the development of more sensitive methods is of crucial importance. Herein we propose the use of hyperpolarized 129Xe nuclear magnetic resonance (NMR) spectroscopy for the sensitive detection of Zn2+ ions. To achieve this goal, the noble gas is encapsulated in dedicated host systems bearing a ligand that chelates the Zn2+ ions. Cryptophanes, aromatic cage molecules made of cyclotriveratrylene groups,[6] are perfectly suited to this purpose as 1) they can easily be rendered water-soluble,[7] 2) the noble gas has a high affinity for their cavity,[8] 3) when xenon is encapsulated, it takes a specific NMR frequency, and 4) xenon exchange in and out of the cavity insures a continuous refreshment of the Xe@ cryptophane environment in hyperpolarization. Such a 129Xe biosensing approach has already been employed for detection of various biological systems, including enzymes [9–11] and nucleic acids.[12] Also, the first in-cell probing of biological events has been achieved: the endocytosis of transferrin could be detected by using 129Xe NMR spectroscopy.[13] All these NMR spectroscopy studies based on the use of hyperpolarized xenon and molecular hosts are characterized by a high sensitivity. However, metal detection is a difficult challenge, which has never been achieved using such an approach.We aimed to design a responsive agent in which the chemical shift of encapsulated xenon would significantly vary when Zn2+ ions are chelated to it. In this manner, a sensitive spectroscopic imaging based on this resonance-frequency variation can be envisioned. For this purpose, we designed sensor 1, which is made of three parts (Scheme1): the cryptophane core hosting xenon, the spacer, and the chelating moiety. A short spacer was chosen to place the chelating moiety near the cryptophane cavity. As a zinc-chelating group we chose nitrilotriacetic acid (NTA), which is easily prepared from l-lysine.[14] Sensor 1 was synthesized from cryptophane 2, which possesses six carboxylate groups ensuring solubility in water at physiological pH value.[7] We were able to activate only one carboxylate group by esterification with N-hydroxysuccinimide. Then, the primary amino …
