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.