Quantitative magnetic resonance fluorine imaging: today and tomorrow

Abstract

Fluorine (19F) is a promising moiety for quantitative magnetic resonance imaging (MRI). It possesses comparable magnetic resonance (MR) sensitivity to proton (1H) but exhibits no tissue background signal, allowing specific and selective assessment of the administrated 19F-containing compounds in vivo. Additionally, the MR spectra of 19F-containing compounds exhibited a wide range of chemical shifts (>200 ppm). Therefore, both MR parameters (e.g., spin-lattice relaxation rate R1) and the absolute quantity of molecule can be determined with 19F MRI for unbiased assessment of tissue physiology and pathology. This article reviews quantitative 19F MRI applications for mapping tumor oxygenation, assessing molecular expression in vascular diseases, and tracking labeled stem cells.

Figure 1

(A) Representative ¹⁹F spectrum of PFPE and PFOB nanoparticles shows the chemical shift of ¹⁹F signatures. The single PFPE peak and five discernible PFOB peaks are easily detected and individually resolved. (B) Chemical structure of PFPE shows its twenty ¹⁹F atoms. (C) Schematic of a PFPE nanoparticle functionalized with homing ligands in the outer phospholipid monolayer (shown in green). The PFPE nanoparticle provides ¹H MR contrast by its surface payload of ~90,000 Gd³⁺ (shown in gold) and ¹⁹F MR contrast by ~100M ¹⁹F in its core. (From Morawski et al. [1] and Southworth et al. [2].)

Figure 2

FREDOM determined pO₂ maps of two representative AT1 tumors in rats. The pO₂ value was calculated pixel-by-pixel based on the quantified ¹⁹F R₁ and a priori calibrated ¹⁹F R₁ - pO₂ curve of HFB. (A and D) Composite ¹⁹F (displayed in color) and ¹H (displayed in grayscale) MR images show HFB distribution in a large tumor (A, 3.6 cm³) and a small tumor (D, 1 cm³). (B and E) Baseline pO₂ maps show higher pO₂ in the small tumor when both animals were breathing air. Mean pO₂ of large and small tumors were 0.1 ± 1.8 torr and 25.4 ± 1.1 torr, respectively. (C and F) Tumor pO₂ maps of same animals obtained at 24 minutes after oxygen breathing, mean pO₂ of large and small tumors were 8.1 ± 4.5 torr and 90.6 ± 3.9 torr, respectively. Both values were significantly higher than that of baseline (p < 0.01). (From Bourke et al. [4].)

Figure 3

(A) A representative ¹⁹F spectrum of PFPE nanoparticle emulsion (−90 ppm) and trichlorofluormethane reference standard (0 ppm) acquired at 4.7 T. (B) The calibration curve for PFPE nanoparticle emulsion shows a linear relationship between the quantity of PFC nanoparticles and ¹⁹F signal intensity. (C) Left: An optical image of a human carotid endarterectomy sample shows moderate luminal narrowing and several atherosclerotic lesions. Middle: A ¹⁹F projection image acquired through the entire thickness of carotid artery sample shows high ¹⁹F signal along the lumen because of the binding of nanoparticles to fibrin. Right: The calculated concentration map of bound nanoparticles in the carotid sample based on ¹⁹F signal intensity in each voxel and the calibrated standard curve in (B). (From Morawski et al. [1].)

Figure 4

Diffusion weighted ¹⁹F signal in the ear of K14-HPV16 mice (open symbols), an animal model of squamous cell cancer with dysplastic lesions developed in the ear epidermis, and in the ear of control C57BL/6 mice (filled symbols). All animals were intravenously injected with of α_vβ₃-integrin targeted PFC nanoparticles before MRI. (A) Results acquired with modest b-values (i.e., an index of diffusion weighting) shows complete decay of ¹⁹F signal in control mouse ears when b-value > 1500 s/mm². In contrast, a large fraction of ¹⁹F signal persisted in the ears of K14-HPV16 mice at all b-values, reflecting the specific binding of targeted nanoparticles to the ear neovasculature of K14-HPV16 mice. (B) Diffusion weighted ¹⁹F signal in the ears of K14-HPV16 mice persisted even when b-values > 10,000 s/mm². (From Waters et al. [5].)

Figure 5

Localization of PFC nanoparticles labeled cells in mice using ¹⁹F MRI. (A) ¹⁹F MRI trafficking of stem/progenitor cells labeled with either PFOB (green) or PFPE (red) nanoparticles. Labeled cells were locally injected into the skeletal muscle of mouse thigh before MRI. (B–D) At 11.7T field strength, ¹⁹F spectral discrimination permits respective imaging of ~1×10⁶ PFOB-loaded cells (B) and PFPE-loaded cells (C). The composite ¹⁹F (displayed in color) and ¹H (displayed in grayscale) image (D) reveals the location of PFOB labeled cells in the left leg and PFPE labeled cells in the right leg (dashed line indicates 3×3 cm² field of view for ¹⁹F images). (E) Similarly, a ¹⁹F image acquired at 1.5T field strength shows ¹⁹F signal from ~4×10⁶ PFPE nanoparticles labeled cells. (F) The composite ¹⁹F and ¹H image shows the location of PFPE nanoparticles labeled cells in a mouse thigh. Overall, the absence of background signal in ¹⁹F images (B, C, and E) enables unambiguous localization of PFC-containing cells at both 1.5 T and 11.7 T field strength. (From Partlow et al. [3].)