Functionalized 129Xe contrast agents for magnetic resonance imaging

Abstract

The concept of 'xenon biosensor' for magnetic resonance imaging (MRI) was first proposed by a Berkeley team in 2001, with evidence that hyperpolarized 129Xe bound to a biotin-labeled cryptophane can detect streptavidin at much lower concentrations (nM-microM) than is typical for contrast-enhanced MRI experiments. 129Xe biosensors have undergone many recent developments to address challenges in molecular imaging. For example, cryptophanes that exhibit 10-fold higher xenon affinity with distinct 129Xe magnetic resonance spectra have been synthesized. Also relevant are dendrimeric cryptophane assemblies and inorganic zeolites that localize many 129Xe atoms to rare targets. Finally, this article considers biosensors that produce measurable changes in 129Xe chemical shift based upon the activity of oligonucleotides, proteins, or enzymes, and includes the first cell studies.

Figure 1

A) Process of optical pumping to produce hyperpolarized ¹²⁹Xe. B) Schematic representation of hp ¹²⁹Xe NMR spectrum showing (from left) resonances of free xenon gas in aqueous solution, Xe-encapsulated biosensor bound to corresponding bioreceptor, and Xe encapsulated in free biosensor. Legend shows components of biosensor: molecular cage, linker, and recognition moiety.

Figure 2

Alternate mono- and tri-functionalization approaches for attaching targeting moieties, dye molecules, and water-solubilizing groups to cryptophane-A.

Figure 3

A) X-ray crystal structure of CAII bound to benzenesulfonamide-8-bond-linker cryptophane, only one enantiomer shown. Data reveal sulfonamidate coordination to Zn²⁺ (gray atom), and Xe (green atom) bound inside cryptophane. B) Laser-polarized ¹²⁹Xe NMR spectra: (i) 7-bond-linker biosensor free in solution; (ii) biosensor bound to CAI and (iii) CAII.

Figure 4

Cryptophane-tetraRGD biosensor targeting α_vβ₃ integrin. Inset: Uptake of Cy3-labeled biosensor in (A) NCI-H1975 and (B) HFL-1 cells.