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Review
. 2023 Apr 12;1(2):121-139.
doi: 10.1021/cbmi.3c00019. eCollection 2023 May 22.

Label-Free Chemically and Molecularly Selective Magnetic Resonance Imaging

Tianhe Wu  1 , Claire Liu  2 , Anbu Mozhi Thamizhchelvan  1 , Candace Fleischer  1 , Xingui Peng  3 , Guanshu Liu  2   4 , Hui Mao  1
Affiliations
Review

Label-Free Chemically and Molecularly Selective Magnetic Resonance Imaging

Tianhe Wu et al. Chem Biomed Imaging. .

Abstract

Biomedical imaging, especially molecular imaging, has been a driving force in scientific discovery, technological innovation, and precision medicine in the past two decades. While substantial advances and discoveries in chemical biology have been made to develop molecular imaging probes and tracers, translating these exogenous agents to clinical application in precision medicine is a major challenge. Among the clinically accepted imaging modalities, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) exemplify the most effective and robust biomedical imaging tools. Both MRI and MRS enable a broad range of chemical, biological and clinical applications from determining molecular structures in biochemical analysis to imaging diagnosis and characterization of many diseases and image-guided interventions. Using chemical, biological, and nuclear magnetic resonance properties of specific endogenous metabolites and native MRI contrast-enhancing biomolecules, label-free molecular and cellular imaging with MRI can be achieved in biomedical research and clinical management of patients with various diseases. This review article outlines the chemical and biological bases of several label-free chemically and molecularly selective MRI and MRS methods that have been applied in imaging biomarker discovery, preclinical investigation, and image-guided clinical management. Examples are provided to demonstrate strategies for using endogenous probes to report the molecular, metabolic, physiological, and functional events and processes in living systems, including patients. Future perspectives on label-free molecular MRI and its challenges as well as potential solutions, including the use of rational design and engineered approaches to develop chemical and biological imaging probes to facilitate or combine with label-free molecular MRI, are discussed.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic illustration of the disproportion of scientific discoveries, imaging probe development, and clinical molecular imaging applications highlights the challenges in translating research to clinical applications.
Figure 2
Figure 2
Labeled vs label-free strategies for generating MRI contrast, namely the change in water MRI signal. The label-free cellular and molecular MRI employs endogenous chemical and biological probes without using exogenous contrast agents and magnetic material labeled probes.
Figure 3
Figure 3
Examples of in vivo single-voxel MRS applications in different organs and diseases with corresponding metabolite profiles. (A) The spectra collected from the brain tumor (right) and the contralateral normal region (left) show different spectral patterns. Prepared from unpublished data. (B) Spectrum from a lesion from a breast cancer patient gives choline and lipid signals that can be used to assess the malignancy of the tumor. Adapted with permission from ref (38). Copyright 2012 Springer Nature. (C) Multivoxel MRS can also be used for assessing prostate cancer in which spatially distinctive spectra from individual voxels can be extracted and compared. Prepared from unpublished data. (D) MRS signals rising from fat and lipids can be used to map the fat levels in the liver for diagnosis of fatty liver. Prepared from unpublished data. (E) Chemical shift-selective imaging and single-voxel MRS are used to examine the lipid accumulation in the diabetic kidney in a mouse model. Reproduced with permission from ref (61). Copyright 2013 the American Physiological Society.
Figure 4
Figure 4
Maps of the rations of NAA vs Cre and Cho vs Cre derived from multivoxel MRSI or CSI of a brain tumor (A) show the intratumoral heterogeneity of metabolic changes with highly elevated Cho and reduced NAA in relation to Cre in the specific regions that cannot be localized well in T2-weighted MRI. Composed from unpublished data. (B) Whole-brain CSI performed on a recurring GBM identified areas with tumor cells infiltrating beyond the boundary delineated in T2-weighted (T2w) and T1-weighted contrast-enhanced (T1w-CE) MRI. Reprinted in part with permission from ref (47). Copyright 2016 Society for Neuro-Oncology and Oxford University Press.
Figure 5
Figure 5
(A) High-resolution ex vivo NMR analysis of intact brain tumor tissue samples revealed resonance signals rising from different protons of the 2HG molecule and their specific chemical shifts. Reproduced with permission from ref (53). Copyright 2012 Springer-Verlag. (B) Spectroscopic editing methods, such as double quantum coherent acquisition, can detect 2HG in patients carrying tumors with IDH mutation. Reproduced with permission from ref (57). Copyright 2015 American Association for Cancer Research.
Figure 6
Figure 6
Diffusion properties of water are used to quantitatively assess the integrity of the cell and tissue in (A) ischemic brain. Adapted with permission from ref (72). Copyright 1999 American Academy of Neurology. (B) Change of ADC in a prostate lesion (circled), and (C) quantitative measurement of diffusion properties in a brain tumor that responded to the treatment before relapsing. Adapted with permission from ref (75). Copyright 2010 Wiley-Liss, Inc.
Figure 7
Figure 7
ASL perfusion MRI from a patient (A) with a brain tumor that is contrast-enhanced in T1 weighted imaging (top row) and increased rCBF (bottom row). Composed from unpublished data. (B) In patients receiving renal transplants, ASL perfusion MRI provides functional and quantitative assessments of the renal filtration, showing a normal blood perfusion map (left) and impaired blood perfusion of the kidney (right). T2 weighted image was used to place the slice (red line) where the labeling RF was applied. Reprinted with permission from ref (80). Copyright 2022 Springer Nature.
Figure 8
Figure 8
Multiecho T2 weighted GRE MRI of kidneys were used to derive BOLD R2*, i.e., 1/T2*, maps (A) of a normal individual (top row), a patient with IgA glomerulonephritis and mild renal impairment (middle row) and a patient with IgA glomerulonephritis and moderate to severe renal impairment (bottom row). The gradual increase of R2* (blue to green) indicates lower oxygenation correlated with the aggravation of renal impairment. Reprinted with permission from ref (83). Copyright 2018 Springer Nature. (B) BOLD MRI with carbogen challenge in a patient with diffuse liver masses in the right posterior lobe shown in T2 weighted MRI and angiography (arrows in the top row). Compared with T2* mapping (left panel) prior to carbogen breathing, the T2* value of the larger lesion is mildly increased (right panel), suggesting that the tumor has heterogeneous hypoxic regions. Reprinted with permission from ref (84). Copyright 2015 Spandidos Publications.
Figure 9
Figure 9
(A) Cerebral venous blood vessels are highlighted in the QSM of the brain. (B) SWI revealed the microbleeds that cannot be clearly delineated in T2 and T2* weighted MRI. A, B: Adapted with permission from ref (85). Copyright 2021 Radiological Society of North America. (C) Iron deposition in the thalamus of a PD patient led to hyperintense signals in QSM and R2* map. Reprinted with permission from ref (86). Copyright 2016 PLosOne. (D) Enhanced MS lesions in QSM due to iron uptake by microglia are correlated to the inflammation-related hyperintensity shown in the T2 weighted image. Reprinted with permission from ref (87). Copyright 2018 American Society of Neuroradiology.
Figure 10
Figure 10
(A) Schematic illustration of the CEST imaging of slow exchange of hydrogen-bound water on amide protons and bulk water. An example of APT imaging of an acute stroke patient with right MCA occlusion (B) with conventional FLAIR and DWI images (top) showing the ischemic region. MTR asymmetry analysis and APT (bottom) showed much clearer ischemic contrasts than MTRasym (3.5 ppm). (C) Z-spectra and MTRasym spectra were obtained from the contralateral normal (black) and the ischemic lesion (red). B, C: Adapted with permission from ref (106). Copyright 2017 International Society for Magnetic Resonance in Medicine and Wiley.
Figure 11
Figure 11
(A) Schematic representation of brain Z-spectrum with typical contributions including direct water saturation (DS), magnetization transfer contrast (MTC), amideNOE, aromaticNOE, aliphaticNOE, amideCEST, CrCEST, PCrCEST, hydroxylCEST, and amineCEST. The DS component is also included in the amineCEST and hyroxylCEST line shapes for reference only. The CEST contributions are plotted in B–E. (B) The non-CEST saturation transfer processes contribute to the brain Z-spectrum. MTC is a strong and broad signal centering around −3.5 to −3 ppm. Amide and aromatic NOE peaks are distributed from 2 to 5 ppm, while aliphaticNOE centers are at −3.5 to −3 ppm. (C) The CEST signals from the protons with slow to intermediate exchange rates (e.g., ArgCEST and CrCEST at 2 ppm, amideCEST at 3.5 ppm, and PCrCEST at 2 and 2.5–2.6 ppm). (D) The peak locations of the amine protons from glutamate (3 ppm) and protein (2.7 ppm), as well as hydroxyl protons (1 ppm). (E) The amine and hydroxyl CEST signal coalesce with the water peak due to higher exchange rates (>1000 s–1). A–E: Reproduced with permission from ref (115). Copyright 2022 John Wiley and Sons, Ltd.
Figure 12
Figure 12
3T D2O MRI can guide the intervention for the hyperosmotic opening of BBB in a dog. (A) T2w image preinjection. (B) D2O MRI contrast-enhancement map. (C) SPIO MRI contrast-enhancement map. (D) Gd-contrast-enhancement map after the administration of mannitol. (E) Correlation between SPIO- and D2O-MRI. The Spearman coefficient (r) = 05350. (F) Correlation between Gd- and D2O- MRI. The Spearman coefficient (r) = 0.6009. Reprinted with permission from ref (142). Copyright 2021 Ivyspring International Publisher.
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