A sensitive PARACEST contrast agent for temperature MRI: Eu³⁺‐DOTAM‐glycine (Gly)‐phenylalanine (Phe)

Abstract

Tissue temperature is a fundamental physiological parameter that can provide insight into pathological processes. The purpose of this study was to develop and characterize a novel paramagnetic chemical exchange saturation transfer (CEST) agent suitable for in vivo temperature mapping at 9.4T. The CEST properties of the europium (Eu 3؉ ) complex of the DOTAMGlycine (Gly)-Phenylalanine (Phe) ligand were studied in vitro at 9.4T as a function of temperature, pH, and agent concentration. The transfer of magnetization (CEST effect) from the bound water to bulk water pools was ϳ75% greater for Eu 3؉ -DOTAMGly-Phe compared to Eu 3؉ -DOTAM-Gly at physiologic temperature (38°C) and pH (7.0 pH units) when using power level sufficiently low for in vivo imaging. Unlike Eu 3؉ -DOTAM-Gly, whose CEST effect decreased with increasing temperature in the physiologic range, the CEST effect of Eu 3؉ -DOTAM-Gly-Phe was optimal at body temperature. A strong linear dependence of the chemical shift of the bound water pool on temperature was observed (0.3 ppm/°C), which was insensitive to pH and agent concentration. Temperature maps with SDs < 1°C were acquired at 9.4T in phantoms containing: 1) phantom A, an aqueous solution of 10 mM Eu 3؉ -DOTAM-Gly-Phe; 2) phantom B, 5% bovine serum albumin ( Tissue temperature and pH are important physiological parameters that are closely related to tissue metabolism. Therefore, noninvasive techniques to measure these parameters have many medical applications (1-5), including for cancer and stroke. For example, tumor temperature can be related to the pathological processes within the tumor (1), while knowledge of tumor pH may aid in diagnosis and in choosing appropriate chemotherapeutic agents. Such agents are weak acids or bases, therefore, their accumulation within cells and, hence, their efficacy depends on the transmembrane pH gradient (4,5). In vivo tissue temperature measurements are often made with invasive probes (i.e., thermocouples), which provide high sensitivity and temporal resolution in localized regions but cannot monitor a whole organ simultaneously. More recently, noninvasive methods for temperature measurement using magnetic resonance imaging (MRI) have been developed (2). These methods are based mainly on the temperaturedependence of the NMR T 1 relaxation time, chemical shift, or diffusion coefficient of water protons (2). Among these MR methods, relating the chemical shift of water protons to temperature is the most widely used. However, the low temperature sensitivity (ϳ0.01 ppm/°C) of this technique limits its application to situations with large temperature variations.More recently, the feasibility of MR thermometry based on the strong temperature dependence of the chemical shifts of paramagnetic lanthanide (Ln) complexes has been explored (3). More specifically, the process of chemical exchange saturation transfer (CEST), in conjunction with paramagnetic lanthanide complexes (i.e., PARACEST), can be used to create high-resolution temperature maps with greater sensitivity tha...

Optimized MRI contrast for on‐resonance proton exchange processes of PARACEST agents in biological systems

“…Our previous study showed that a 5-mM concentration of the PARACEST agent Eu 3ϩ -DOATM-Gly-phenylalanine was necessary to generate a clear CEST contrast of ϳ2% in brain tissue or tissuelike samples (17). The sensitivity of both PARACEST and OPARACHEE methods will vary in different tissue types due to the MT effects from endogenous macromolecules (23,38).…”

“…The advantages of the OPARACHEE method compared to the conventional PARACEST method are the greater sensitivity, low power requirements and consequently low specific absorption ratio, and the insensitivity of the method to the bound-water chemical shift. However, most applications of PARACEST agents are based on the measurement of the chemical shifts of bound protons and/or the detection of bound proton CEST contrast (13,16,17). The OPARACHEE method will likely find utility in the detection of targeted agent uptake into tissue.…”

“…The magnetization in each pool can be described by the modified Bloch equations incorporating chemical exchange. For a four-pool model (assuming the irradiation RF field is in the x-direction with 0 phase and -x direction with phase in the rotating frame) incorporating a WALTZ-16 pulse train, we can write: [12] where [15] k 1a ϭ 1/T 1a ϩ k ab ϩ k ac ϩ k ad [16] k 1b ϭ 1/T 1b ϩ k ba [17] FIG. 6.…”

“…Diamagnetic and paramagnetic chemical exchange saturation transfer (PARACEST) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) agents have many possible medical and biologic applications, including the measurement of tissue pH based on the pH dependence of the exchange rate of amide protons with bulk water protons (13)(14)(15), the measurement of tissue temperature using the linear dependence of the bound water chemical shift on temperature (16,17), enzymatic activity (18), and metabolite levels (19)(20)(21). The CEST detection sensitivity (or CEST effect) is defined as the change in the bulk water signal intensity of the agent solution following irradiation of the exchangeable protons.…”

“…Despite the large chemical shift of the bound water and amide protons associated with PARACEST agents, the relatively high saturation power needed for in vivo PARAC-EST imaging results in the simultaneous observation of inherent magnetization transfer (MT) from macromolecule-bound protons (17,23). Though dysprosium-, thulium (Tm 3ϩ )-, and ytterbium-based PARACEST agents have bound water chemical shifts beyond the MT effect range, the fast proton exchange between the bound water of these compounds and the bulk water results in an undetectable CEST signal within specific absorption rate power limits.…”