Abstract:
An imaging contrast agent is provided for hydrogen magnetic resonance imaging (H MRI). The agent uses replacement and chemical exchange of hydrogen (H) and deuterium (D) on obtaining MRI images for comparison. An isotonic physiologic saline solution with deuterium oxide (D 2 O) is made. The solution is intravenously injected to obtain the intensity alterations on MRI images. The injected D 2 O is perfused into tissue and replace the original water. Exchanges between H and D occur and a solution of hydrogen deuterium oxide (HDO) is obtained. After such mechanisms, MRI images are compared for differences. Thus, a novel, non-radioactive, non-toxic and non-invasive MRI agent is provided for people who are allergic to general imaging agents.

Description:
TECHNICAL FIELD OF THE INVENTION 
       [0001]    The present invention relates to an imaging contrast agent; more particularly, relates to using replacement effect and chemical exchange effect of heavy water (deuterium oxide, D 2 O) in normal water (H 2 O) as a mechanism for dynamic magnetic resonance imaging (MRI) detection by comparing images before and after administration D 2 O. 
       DESCRIPTION OF THE RELATED ARTS 
       [0002]    Cerebral blood flow (CBF) is a specific flow amount of arterial blood to microvascular bed in a tissue, which is usually expressed in unit of ml/(100 g-min). CBF has deep influence on physiological environment, including supplement of glucose and adjustment of pH value. In an MRI image, a gadolinium(Gd)-containing imaging agent (Gd-DTPA) is mostly often used for obtaining data of cerebral blood perfusion. However, the shortcomings of Gd-DTPA should be taken into account. Gd-DTPA is an intravascular tracer which is more suitable for cerebral blood volume (CBV) measurement. On the other hand, there is an allergy problem to certain patients. It is revealed by James Varani, Marissa DaSilva, et al in “Effects of gadolinium-based magnetic resonance imaging imaging agents on human skin in organ culture and human skin fibroblasts,” Inves Radio, 44: 74-81, 2009, that GD-DTPA is possible to cause nephrogenic systemic fibrosis (NSF) to patients having Kidney diseases. 
         [0003]    Deuterium (D) is a stable isotope of hydrogen (H). As is revealed in “Deuterium NMR tissue perfusion measurements using the tracer uptake approach: II. Comparison with microspheres in tumors,” Magn Reson Med 42: 240-247, 1999, by Nicholas E. Simpson and Jeffrey L. Evelhoch, heavy water is often used in MRI as a diffusible tracer for perfusion measurement under a larmor frequency of 6.53 MHz/T. But, owing to different coils, information thus obtained in MRI has low signal-to-noise ratio (SNR). 
         [0004]    In addition, it is also revealed in “Arterial spin labeling perfusion MRI in pediatric arterial ischemic stroke: initial experiences,”  J Magn Reson Imag  29: 283-290, 2009, by Juan Chen, Daniel J. Licht, et al, that, for patients who are allergic to Gd-DTPA, arterial spin labeling (ASL) is another choice for perfusion MRI. Therein, arterial blood is used as an endogenous tracer and ASL becomes a safe and non-invasive method for CBF. Yet, the limitation for ASL is low signal change. Under an optimal tracer labeling, signal change only achieves at the level of 4%. 
         [0005]    Hence, the prior arts do not fulfill all users&#39; requests on actual use. 
       SUMMARY OF THE INVENTION 
       [0006]    The main purpose of the present invention is to use the replacement effect and chemical exchange effect of D 2 O as contrast mechanism for hydrogen (H) MRI. Blood flow can be assessed by dynamic MRI detection and comparing images before and after the administration of D 2 O. 
         [0007]    The second purpose of the present invention is to provide a fast, non-radioactive, non-toxic and non-invasive agent used in perfusion MRI for patients who are unsuitable for general imaging agents. 
         [0008]    The third purpose of the present invention is to make an isotonic physiologic saline solution containing heavy water as contrast agent for H MRI. The H signal properties, including proton density, T1, and T2, can be changed and thus generated image contrast. 
         [0009]    To achieve the above purposes, the present invention is a contrast agent of D 2 O for H MRI. By administration of D 2 O into tissue, part of the H 2 O can be replaced by D 2 O and therefore reduced the proton density property of H MRI. The D 2 O and H 2 O have chemical exchange effect and generate HDO. The HDO slows the T1 and T2 relaxation rates of H MRI. By affecting the proton density, T1, and T2, the signal intensities of H MRI can be altered. Accordingly, a novel agent using replacement effect and chemical exchange effect of heavy water for H MRI is obtained. 
     
    
     
       BRIEF DESCRIPTIONS OF THE DRAWINGS 
         [0010]    The present invention will be better understood from the following detailed description of the preferred embodiment according to the present invention, taken in conjunction with the accompanying drawings, in which 
           [0011]      FIG. 1A  is the view showing the T1 relaxation rate R1 in concentration phantom; 
           [0012]      FIG. 1B  is the view showing the T2 relaxation rate R2 in concentration phantom; 
           [0013]      FIG. 2A  is the view showing the consecutive MRI images; 
           [0014]      FIG. 2B  is the view showing the curve of signal change; 
           [0015]      FIG. 3A  is the view showing the brain image before injecting D 2 O; 
           [0016]      FIG. 3B  is the view showing the brain image after injecting D 2 O; and 
           [0017]      FIG. 4  is the view showing the curves of signal change of D 2 O and Gd-DTPA. 
       
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENT 
       [0018]    The following description of the preferred embodiment is provided to understand the features and the structures of the present invention. 
         [0019]    The present invention is a contrast agent of heavy water (D 2 O) for hydrogen magnetic resonance imaging (H MRI), where H MRI indirectly detects the deuterium (D) by measuring the difference of image intensities before and after administration of D 2 O. According to the theory of nuclear magnetic resonance, the signal-to-noise ratio (SNR) is improved by indirectly detection since the H sensitivity is 100 times higher than the D. 
         [0020]    The present invention uses D 2 O as a blood tracer for H MRI perfusion imaging. A solution of D 2 O is intravenously injected into a living tissue or organ during consecutive H MRI acquisitions. D 2 O is injected at an amount of 0.1˜20% of weight of the living object. 
         [0021]    After injection of D 2 O, the D 2 O will be perfused to living tissue or organ by blood perfusion, and thus the image intensity of H MRI will be changed. There are two mechanisms to induce signal alteration. First, the blood perfusion will replace the original H with D. The total amount of H in imaging voxels will be reduced by this replacement effect. The decreased density of H will reduce the signal intensities of H MRI. Second, a chemical exchange phenomenon will occur between H and D and slow the T1 and T2 relaxation of H. Due to similar physical and chemical properties of D and H, the introduction of D 2 O into H 2 O results in an isotopic H-D exchange and leads to a production of semi-heavy water HDO by the following reaction: 
         [0000]    
       
         
           
             
               
                 
                   
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         [0000]    Therein, K is equilibrium constant experimentally determined by NMR, mass spectroscopy, and near-infrared spectroscopy and is approximate to 4 in liquid phase. The H on the HDO has slower T1 and T2 relaxation than original HDO. The averaged T1 and T2 relaxation rate are therefore decreased and further alter the image intensities. 
         [0022]    Please refer to  FIG. 1A  and  FIG. 1B , which are views showing the T1 and T2 relaxation rates of H are linearly decreased with the D 2 O concentration. The R1 and R2 in the vertical axis are the relaxation rates of T1 and T2 relaxation, respectively. The negative slopes of these two figures show that the present invention induces negative relaxivities for 1H MRI. 
         [0023]    In a experimental phantom with D 2 O concentration as c, respective concentrations of H 2 O, HDO, and D 2 O are (1-c) 2 , 2c(1-c), and c 2 , where a part of c of H is replaced by D. Population ratio of H coupled H and D coupled H is calculated as (1-c):c. The observed T1 and T2 relaxation rates are the population weighted sums of all H. Since the D coupled H has slower relaxation rates than H coupled H, we observe linear relations of R1 and R2 as changing the D 2 O concentration c in  FIG. 1A  and  FIG. 1B . 
         [0024]    For application of the present invention for perfusion assessment, an isotonic physiologic saline solution containing D 2 O is made to be intravenously injected into a living object for H MRI. 
         [0025]    Please refer to  FIG. 2A  and  FIG. 2B , which are views showing consecutive MRI images and a curve of signal change. As shown in the figures, 6 normal adult Sprague-Dawley rats (˜200-310 g) are used. Each rat is anesthetized with 1.5% isoflurane/air via a nose cone with respiratory monitoring. Tail vein catheterization is performed with a 0.8-m long polyethylene tube connected to a 23-gaude needle, where a dead volume in a catheter is about 0.2 ml. On operating, 1.5 mL of D 2 O (99.8%, Cambridge Isotope, Woburn, Mass.) is manually injected into tail vein. After injecting, the catheter is flushed with 0.5 mL 0.9% NaCl solution. For comparison, an additional 0.2 mL Gd-DTPA (Magnevist) is manually injected into tail vein while D 2 O scanning is completed after 10 min. After injection, the catheter is flushed with 0.5 mL 0.9% NaCl solution. In vivo brain imaging is performed in prone position. All images are acquired on a 4.7 animal MRI scanner (Bruker Biospec 47/40). The parameters for the dynamic images are as follow: TR/TE/θ=1000 ms/30 ms/90 degree, FOV=2.9 cm, matrix size=128×128, and slice thickness=1 mm. 
         [0026]    Averaged signals from whole brain are portrayed as a signal-intensity curve. For comparison, the signal-intensity curve is transferred into a percentage change curve according to the following formula: 
         [0000]    
       
         
           
             
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         [0027]    Therein, S(t) is a signal at time t and S0 is a signal before using the contrast agent. Expression of data analysis is shown in  FIG. 2A  and  FIG. 2B . After manually selecting the whole brain as ROI in  FIG. 2A , the dynamic points are plotted as signal intensity curves and then transferred into the signal change curves as shown in  FIG. 2B . 
         [0028]    Please refer to  FIG. 3A  and  FIG. 3B , which are views showing brain images before and after injecting D 2 O. As shown in the figures, after D 2 O injection, original H 2 O are replaced by D 2 O. Because of the replacement effect and chemical exchange effect, the signal intensities decreased as shown in  FIG. 3A  to  FIG. 3B . 
         [0029]    Please refer to  FIG. 4 , which is a view showing curves of signal change of D 2 O and Gd-DTPA. As shown in the figure, a curve of signal change for D 2 O 1 and a curve of signal change for Gd-DTPA 2 are displayed. Although the signal change for D 2 O injection is not as strong as that of Gd-DTPA, the signal change of 10% is good enough for the measurement of tissue perfusion. 
         [0030]    D 2 O is not toxic to animals as long as the amount of injecting D 2 O is less than 20% of body weight. The injected D 2 O is about 0.6% of body weight in the present invention. It is much lower than the tolerable dosage. From the results, the signal change of D 2 O achieves at the level of 10%. It is more superior to that of arterial spin labeling (ASL). 
         [0031]    Thus, the present invention uses a non-toxic and diffusible imaging agent, D 2 O, to be injected into an animal (e.g. rat) for obtaining cerebral blood flow (CBF). In addition, D 2 O is a potential contrast agent in perfusion MRI for patients who are unsuitable for Gd-DTPA. Accordingly, the present invention provides a fast, non-radioactive, non-toxic and non-invasive agent for MRI. To sum up, the present invention is an agent using heavy water for hydrogen magnetic resonance imaging, where replacement effect and chemical exchange effect of D 2 O are used as mechanisms for image contrast; D 2 O is a potential contrast agent in perfusion MRI for patients who are unsuitable for Gd-DTPA; and, thus, the present invention provides a fast, non-radioactive, non-toxic and non-invasive agent for MRI. 
         [0032]    The preferred embodiment herein disclosed is not intended to unnecessarily limit the scope of the invention. Therefore, simple modifications or variations belonging to the equivalent of the scope of the claims and the instructions disclosed herein for a patent are all within the scope of the present invention.