Chemical exchange saturation transfer imaging of creatine, phosphocreatine, and protein arginine residue in tissues

Abstract

Chemical exchange saturation transfer (CEST) MRI has become a promising technique to assay target proteins and metabolites through their exchangeable protons, noninvasively. The ubiquity of creatine (Cr) and phosphocreatine (PCr) due to their pivotal roles in energy homeostasis through the creatine phosphate pathway has made them prime targets for CEST in the diagnosis and monitoring of disease pathologies, particularly in tissues heavily dependent on the maintenance of rich energy reserves. Guanidinium CEST from protein arginine residues (i.e. arginine CEST) can also provide information about the protein profile in tissue. However, numerous obfuscating factors stand as obstacles to the specificity of arginine, Cr, and PCr imaging through CEST, such as semisolid magnetization transfer, fast chemical exchanges such as primary amines, and the effects of nuclear Overhauser enhancement from aromatic and amide protons. In this review, the specific exchange properties of protein arginine residues, Cr, and PCr, along with their validation, are discussed, including the considerations necessary to target and tune their signal effects through CEST imaging. Additionally, strategies that have been employed to enhance the specificity of these exchanges in CEST imaging are described, along with how they have opened up possible applications of protein arginine residues, Cr and PCr CEST imaging in the study and diagnosis of pathology. A clear understanding of the capabilities and caveats of using CEST to image these vital metabolites and mitigation strategies is crucial to expanding the possibilities of this promising technology.

Guanidinium and amide CEST mapping of human brain by high spectral resolution CEST at 3 T

“…Once the saturation B 1 passes the optimum value, the CEST signals decrease dramatically because of the MTC scaling, which has been well explained previously. 16,39 The GuanCEST signal at the high field include both protein ArgCEST signal and CrCEST signal. 7,8 At 3 T MRI, the CrCEST can still contribute to the GuanCEST signal as the exchange rate of the CrCEST was established to be less than 400 s −1 in brain by the latest study.…”

“…[11][12][13][14][15] This method, however, still has interference from amide and aromatic NOE and other fast-exchanging amine and hydroxyl protons between 0 and 5 ppm, as summarized in the recent review. 16 The extrapolated semisolid magnetization transfer reference (EMR) method further improved the Lorentzian fitting approach 17,18 ; nevertheless, it still faces the same issue as the Lorentzian fitting approach, i.e., mixed CEST signals are present because of the high saturation powers applied. [17][18][19] Although the signals at 3.5 ppm extracted by the above 3 methods are mixed CEST contrasts, they can still be used for tissue protein profiling because all those CEST contrasts come from protein derivatives.…”

“…Instead of conventional asymmetry analyses, one relatively new strategy has been applied to acquire a full Z ‐spectrum with low saturation field strength B 1 and fit it by assuming a Lorentzian line‐shape for each contributing signal, such as direct saturation (DS), guanidinium (Guan), amide, amine, and nuclear Overhauser effect (NOE) peaks 11–15 . This method, however, still has interference from amide and aromatic NOE and other fast‐exchanging amine and hydroxyl protons between 0 and 5 ppm, as summarized in the recent review 16 . The extrapolated semisolid magnetization transfer reference (EMR) method further improved the Lorentzian fitting approach 17,18 ; nevertheless, it still faces the same issue as the Lorentzian fitting approach, i.e., mixed CEST signals are present because of the high saturation powers applied 17–19 .…”

“…AmideCEST and ArgCEST are among a few CEST contrasts that can be extracted with high confidence from the crowded in vivo Z ‐spectrum because of their low exchange rates (∼60‐70 Hz) 33 . Because the mixed signal always complicates ArgCEST with creatine and phosphocreatine CEST (CrCEST/PCrCEST) at 2 ppm, 16 the CEST peak at this range is named collectively as GuanCEST. Interestingly, GuanCEST is visible at the high field MRI (>7 T) on both animal 6–8,11,32 and human brains 15,23,34 .…”

The exchange rates of amide and arginine guanidinium CEST in the mouse brain

“…It is noteworthy that amideCEST should be distinguished from APT-weighted MRI, which also focuses on the peak at 3.5 ppm but is obtained by asymmetry analysis of the Zspectrum and thus includes multiple other effects including those from relayed NOEs (rNOEs) and asymmetry in the semisolid magnetization transfer contrast (MTC) (6). Guanidinium (Guan) CEST was reported in creatine (Cr) phantoms (7)(8)(9), muscle (10)(11)(12)(13), and brain (14), the Zspectrum of which at 2 ppm also includes the phosphocreatine (PCr) and the guanidinium protons of arginine groups in endogenous mobile proteins (5,(15)(16)(17)(18). Since for proteins the only guanidinium group exists in Arginine (Arg) groups, we name the GuanCEST signal from proteins as ArgCEST, while Cr as CrCEST.…”