Phenols as Diamagnetic T₂‐Exchange Magnetic Resonance Imaging Contrast Agents

Abstract

Although T -exchange (T ) NMR phenomena have been known for decades, there has been a resurgence of interest to develop T MRI contrast agents. One indispensable advantage of T MR agents is the possibility of using non-toxic and/or bio-compatible diamagnetic compounds with intermediate exchangeable protons. Herein a library of phenol-based compounds is screened and their T contrast (exchange relaxivity, r ) at 9.4 T determined. The T contrast of phenol protons allows direct detection by MRI at a millimolar concentration level. The effect of chemical modification of the phenol on the T MRI contrast through modulation of exchange rate and chemical shift was also studied and provides a guideline for use of endogenous and exogenous phenols for T MRI contrast. As a proof-of-principle application, phenol T contrast can be used to detect enzyme activity in a tyrosinase-catalyzed catechol oxidation reaction.

Triazoles as T2‐Exchange Magnetic Resonance Imaging Contrast Agents for the Detection of Nitrilase Activity

“…[12] The two-phase pH dependence of k ex of 1 is markedly different from other reported protons such as phenol. [13] At pH 7.0, the k ex was estimated to be 27.3 AE 4.0 kHz, which is close to the Dw of 1 [i.e.,2 p 9.2 (ppm) 400 (Hz ppm À1 ) = 23.1 10 3 rad s À1 ], enabling the highest enhancement (r 2ex = 0.10 s À1 mm À1 ). It should be noted that our assumption that the temperature dependence of the exchangeable protons follows the Arrhenius equation is valid only for one-step ex- change model and caution should be taken when the exchange model involves two steps such as those of salicylic acid.…”

“…In order to determine the k ex values, we measured r 2ex values at three temperatures (i.e., 20, 30, and 37 °C) and fitted them to Equation (1) at each pH (Figures D and E), under the assumption that k ex increases with temperature (Figure S4) . The two‐phase pH dependence of k ex of 1 is markedly different from other reported protons such as phenol . At pH 7.0, the k ex was estimated to be 27.3±4.0 kHz, which is close to the Δ ω of 1 [i.e., 2π×9.2 (ppm)×400 (Hz ppm −1 )=23.1×10 3 rad s −1 ], enabling the highest enhancement ( r 2ex =0.10 s −1 m m −1 ).…”

“…T 2ex MRI contrast can be utilized to develop responsive agents for specific detection of biomarkers and enzymes, for example, nitric oxide and tyrosinase . Such an MRI detection can be achieved when a biomarker or enzyme acts on the exchangeable protons, either by enhancing (by the so‐called “turn‐on” mechanism) or attenuating (by the “turn‐off” mechanism) the T 2ex contrast.…”

“…To date, the T 2ex principle has been successfully extendedt oafew diamagnetic compounds, including glycogen, [10] iopamidol, [11] glucose, [12] andp henols. [13] The feasibility of the in vivo applications of T 2ex agents has been demonstrated by ar ecently published T 2 -weightedd ynamic contrast-enhancedM RI (DCE-MRI) study in which d-maltose was used as the contrast agent to characterize the permeability of tumors. [14] However,t he limited Dw (typically < 6ppm) createsasensitivityb arrierf or most diamagnetica gents (r 2ex < 0.1 s À1 mm À1 ).…”

Carbon Dots as a New Class of Diamagnetic Chemical Exchange Saturation Transfer (diaCEST) MRI Contrast Agents

“…At pH 7.4, the Z-spectra show am ore attenuated signal at the positive frequency offset when increasing the concentration of AC-dots from 0.5 to 10 mg mL À1 ,w hile the MTR asym plots indicate an increase in CEST signal for all concentrations.A t1 0mgmL À1 of ACdots,the maximum MTR asym intensity was observed at 2ppm, consistent with the diaCEST contrast of the guanidinium protons of arginine (Supporting Information, Figure S5). [29] To demonstrate that the CEST effect is indeed an inherent feature of hydrophilic carbon dots,weprepared and B,C) Mass concentration-dependence of Z-spectra (B, relative water signal with and without saturation) and MTR asym spectra (C, asymmetry calculationo fZ-spectra relative to water frequency at 0ppm) for 0.5-10 mg mL À1 AC-dots at pH 7.4. The MTR asym signal at 2ppm is also af unction of saturation field strength (B 1 )and saturation time (t sat ), as shown in Figure S6 in the Supporting Information.…”