title: Parahydrogen-induced polarization (PHIP) hyperpolarized MR receptor imaging in vivo: a pilot study of 13C imaging of atheroma in mice.
abstract: MR techniques using hyperpolarized (13)C have successfully produced examples of angiography and intermediary metabolic imaging, but, to date, no receptor imaging has been attempted. The goal of this study was to synthesize and evaluate a novel hyperpolarizable molecule, 2,2,3,3-tetrafluoropropyl 1-(13)C-propionate-d(2,3,3) (TFPP), for the detection of atheromatous plaques in vivo. TFPP binds to lipid bilayers and its use in hyperpolarized MR could prove to be a major step towards receptor imaging. The precursor, 2,2,3,3-tetrafluoropropyl 1-(13)C-acrylate-d(2,3,3) (TFPA), binds to 1,2-dimyristoylphosphatidylcholine lipid bilayers with a 1.6-ppm chemical shift in the (19)F MR spectrum. This molecule was designed to be hyperpolarized through the addition of parahydrogen to the (13)C-acrylate moiety by parahydrogen-induced polarization. TFPA was hyperpolarized to TFPP to an extent similar to that of the hydroxyethylacrylate to hydroxyethylpropionate transition: 17 ± 4% for TFPP versus 20% for hydroxyethylpropionate; T(1) relaxation times (45 ± 2 s versus 55 ± 2 s) were comparable and the hyperpolarized properties of TFPP were characterized. Hydroxyethylacrylate, like TFPA, has a chemical structure with an acrylate moiety, but does not contain the lipid-binding tetrafluoropropyl functional group. Hyperpolarized TFPP binds to the lipid bilayer, appearing as a second, chemically shifted (13)C hyperpolarized MR signal with a further reduction in the longitudinal relaxation time (T(1) = 21 ± 1 s). In aortas harvested from low-density lipoprotein receptor knock-out mice fed with a high-fat diet for 9 months, and in which atheroma is deposited in the aorta and heart, TFPP showed greater binding to lipid on the intimal surface than in control mice fed a normal diet. When TFPP was hyperpolarized and administered in vivo to atheromatous mice in a pilot study, increased binding was observed on the endocardial surface of the intact heart compared with normally fed controls. Hyperpolarized TFPP has bio-sensing specificity for lipid, coupled with a 42,000-fold sensitivity gain in the MR signal at 4.7 T. Binding of TFPP with lipids results in the formation of a characteristic second peak in MRS. TFPP therefore has the potential to act as an in vivo molecular probe for atheromatous plaque imaging and may serve as a model of receptor-targeted bio-imaging with enhanced MR sensitivity.
authors.affiliation: Enhanced Magnetic Resonance Laboratory, Huntington Medical Research Institutes, Pasadena, CA 91105, USA. pratip@hmri.org
authors.forename: Pratip
authors.initials: P
authors.lastname: Bhattacharya
authors.forename: Eduard Y
authors.initials: EY
authors.lastname: Chekmenev
authors.forename: Wanda F
authors.initials: WF
authors.lastname: Reynolds
authors.forename: Shawn
authors.initials: S
authors.lastname: Wagner
authors.forename: Niki
authors.initials: N
authors.lastname: Zacharias
authors.forename: Henry R
authors.initials: HR
authors.lastname: Chan
authors.forename: Rolf
authors.initials: R
authors.lastname: Bünger
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
mesh_terms: D000818:Animals; D006859:Hydrogen / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D011700:Putrescine / Q000031:analogs & derivatives / Q000378:metabolism; D011973:Receptors, LDL / Q000032:analysis* / Q000172:deficiency
chemical_list: D011973:Receptors, LDL; C049506:2,2,3,3-tetrafluoroputrescine; D006859:Hydrogen; D011700:Putrescine