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Ytterbium chelated to 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,10-orthoaminoanilide.

Authors

Pagel M, Chopra A.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2011 Nov 26 [updated 2012 Jan 05].

Excerpt

Many pathologies and biological processes are associated with changes in extracellular pH (pHe). For example, the pHe of the tumor microenvironment can be acidic (pH 6.5–6.9) relative to pHe in normal tissues (pH 7.2–7.4) due to aerobic glycolysis that produces excess lactic acid (1). Accurately measuring tumor pHe may be used to diagnose tumors. Furthermore, acidic tumors are chemoresistant against weak-base chemotherapies such as doxorubicin, and they may be more sensitive to weak-acid chemotherapies (2). Accurately measuring tumor pHe may provide patients and physicians with the ability to select the best chemotherapy for the tumor in order to provide personalized medicine to the patient. Clinical drug trials with experimental weak-base and weak-acid chemotherapies may benefit by stratifying patients on the basis of their tumor pHe. Treatments that modulate pHe, such as bicarbonate, have been shown to reduce metastases and increase survival in mouse models of human mammary carcinoma (3). Chronic administration of excessive bicarbonate, however, may lead to alkalosis of normal tissues, so a method to monitor tissue pHe is needed to support studies of pHe-modulating treatments. Many imaging methods have been developed to measure tumor pHe, including optical imaging, electron paramagnetic resonance (EPR) imaging, positron emission tomography imaging, magnetic resonance (MR) spectroscopy, and hyperpolarized MR imaging (MRI), but these methods suffer from poor depth of penetration, lack of accuracy or precision, produce images with poor spatial resolution, and/or require specialized hardware that is not readily available in the imaging clinic (4). Chemical exchange saturation transfer (CEST) is a novel MRI contrast technique (5) that is an attractive alternative to the T1 and T2 contrast techniques, particularly at high magnetic fields (6). CEST agents possess a hydrogen proton with a moderate to slow exchange rate with water. The concentration required for in vivo imaging is in the ~10 mM range. The specific minimum concentration for each biomedical study depends on characteristics of the tissue, such as the endogenous T1 relaxation time of the tissue and the concentration of water in the tissue that is accessible to the agent. Selective saturation of the MR frequency of this proton, followed by exchange with solvent water, reduces the MR signal of the water. Agents that include a paramagnetic lanthanide ion in the structure shift the MR frequencies of the exchangeable proton to unique values to facilitate selective detection and are known as paramagnetic CEST (PARACEST) agents (7, 8). Endogenous MR contrast may be continually monitored in the presence of PARACEST agents by neglecting to saturate the MR frequency of the exchangeable proton (assuming that the T1 relaxation of the PARACEST agent is negligible). The chemical exchange of a hydrogen atom from the CEST agent to a water molecule is base-catalyzed; therefore, CEST from these chemical functional groups is dependent on the pH of the environment. The possibility of measuring pH with a CEST MRI contrast agent was recognized along with the initial reports of diamagnetic CEST (DIACEST) agents (9). This methodology was subsequently extended to PARACEST agents that contained amide groups (8). The ratio of a pH-dependent CEST effect to a pH-independent CEST effect is used to measure the pH and does not depend on the concentration of the agent (10). Ytterbium chelated to 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,10-orthoaminoanilide (Yb-DO3A-oAA) is an extension of the pioneering work with CEST MRI. This compound can be used to measure the pH-dependent CEST effects from an amide and an amine of the agent, and the ratio of the CEST effects can then be used to measure the pH in a concentration-independent manner (11). The selective saturation of CEST MRI studies is typically applied for 1 to 5 seconds to generate a steady state of saturation (12), which greatly lengthens the time required for in vivo detection of PARACEST MRI contrast agents. Fast imaging methods, such as Rapid Acquisition with Relaxation Enhancement (RARE) and Fast Low Angle SHot (FLASH), reduce the total acquisition time and can be used to offset the long time needed for CEST MRI. The CEST-RARE MRI protocol can acquire an image as quickly as 5.5 seconds, and the CEST-FLASH MRI protocol can acquire an image within 13 seconds, depending on the endogenous T1 relaxation time of the tissue (13). In addition, a second "control" MR image is typically acquired to account for the direct saturation of water by applying selective saturation at a MR frequency with an opposite sign relative to the saturation frequency of the first MR image, whch doubles the total acquisition time to 11 seconds and 26 seconds for CEST-RARE and CEST-FLASH, respectively. This method does not account for B0 inhomogeneity or T2 relaxation effects. Alternatively, MR CEST spectroscopic imaging can be performed by acquiring a series of MR images while iterating the MR frequency of the selective saturation in order to create a CEST spectrum (also known as a Z-spectrum) for each pixel in the image. This method accounts for B0 inhomogeneity and T2 relaxation effects and can more accurately evaluate magnetization transfer effects (14). Typical in vivo CEST spectra require 27 to 61 saturation frequencies for acceptable spectral resolution. The need for multiple CEST MR images to create a CEST spectrum further lengthens the the time required for in vivo detection of CEST agents. However, extremely fast MR acquisition methods, such as Fast Imaging with Steady State Precession (FISP), can be used to acquire a single MR image within 1.3-5.3 seconds (comprising of 1 to 5 seconds for saturation and 0.3 seconds to acquire the image). This fast rate can acquire a series of 27 to 61 CEST MR images within 0.6–5.4 minutes (15). The CEST-FISP MRI protocol was used to detect the accumulation of the PARACEST agent Yb-DO3A-oAA within the tumor tissue of mice bearing human mammary carcinoma MDA-MB-231 cell tumors (16).

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