Logo PTB

MR technology

Research group 8.11

Hyperpolarized 129Xe in Molecular Imaging

Molecular imaging aims to image physiological processes at the molecular level or at the cellular level by detecting directly the substances involved (biomarkers) or their mutual interactions. This requires measurement technologys of extraordinary sensitivity and accuracy as can be achieved in nuclear-magnetic resonance only with the aid of hyperpolarization procedures, for example on the spin 1/2 isotop 129Xe. In conjunction with carrier substances used as contrast agents, hyperpolarized 129Xe enables proof of biomarkers at concentration levels of 1 nanomolar or less in-vitro. The further development of molecular imaging with hyperpolarized 129Xe requires a metrological characterization of measurement procedures in order to develop and establish efficient and quantitative technology. Potential applications of xenon-based contrast agents are in the areas of the in-vitro diagnostics, for example in quantitative biomarker profiling for personalized medicine, and of medical imaging, for example for the early diagnosis of diseases or for the control of therapeutic treatment.

To top

129Xe Biosensors for Immunology

The presentation of exogenous antigens by the main histocompatibility complex II (MHC II) is the first step in the acquired immune response of the organism to foreign matter. To furnish exemplary proof of the antigen bonding by MHC II, the peptide fragment hemagglutinin (HA) of the influenza virus was connected to a molecular cage which is accessible to xenon (cryptophane-A) by a linker (composed of PEG and a tetrameric peptide (GEEG) connected upstream). When the biosensor binds to MHC II via HA, the signal of the hyperpolarized 129Xe, which is encapsulated by this biosensor via cryptophane-A, experiences a position displacement. This spectroscopic proof of the antigen:MHC complex formation can be performed with molecular concentrations in the range of micromolar.

 

 

Scheme of the biosensor bonding to MHC II. Free (blue) or bonded sensors (red) can be discriminated in-vitro in the xenon-NMR spectrum with the aid of differing signals.

Host/guest kinetics of hyperpolarized 129Xe with carrier substances

The container-shaped molecule cryptophane-A has proved its worth as a carrier substance for hyperpolarized 129Xe. It is able to enclose a single xenon atom for some milliseconds and to bond it via functional groups to specific target substances (targeting). In a great number of studies, such biosensors have been used for biomarker or cell recognition; an example can be found here. Due to the reversible binding, the method of saturation transfer between free and enclosed xenon can be applied and thus the limit for furnishing proof of a target substance can – in dependence of the binding kinetics – again be shifted downwards by up to several orders of magnitude. The procedure is essential for performing measurements in the concentration range of biomarkers in native systems (cells, organisms) which are in the nanomolar range and less.

The kinetics of the reversible bonding of hyperpolarized 129Xe to cryptophane-A has recently been cleared up. In an aqueous solution, a degenerated exchange between free and cryptophane-A (or, biosensor-) bound hyperpolarized 129Xe and hyperpolarized 129Xe takes place in addition to a simple dissociative process.

  

Reaction scheme for degenerated exchange: Xenon atoms change the bonding state without an intermittently free cryptophane-A molecule.

For the qualitative and quantitative analysis of bonding kinetics, new measurement procedures have been developed which make use of the magnetization or saturation transfer between free and biosensor-bound hyperpolarized 129Xe as a function of its concentrations.

  

The rate for saturation or magnetization transfer in the cryptophane-A-xenon host-guest system is linearly dependent on the xenon concentration. The kinetic rates for dissociative and degenerated exchange can be quantified from ordinate intercept and slope, respectively.

Cooperation partners

Prof. Dr. C. Freund, Freie Universität Berlin (FUB)

Dr. L. Schröder,  Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)

Dr. T. Riemer, Institut für Medizinische Physik und Biophysik, Medizinische Fakultät der Univ. Leipzig

To top

Selected references

Schlundt, et al.
A Xenon-129 Biosensor for Monitoring MHC–Peptide Interactions
Chem. Int. Ed. 48, 4142 (2009).
Opens external link in new windowDOI: 10.1002/anie.200806149

S. Korchak, W. Kilian, L. Mitschang
Configuration and Performance of a Mobile 129Xe Polarizer
Appl. Magn. Reson. 44, 65 (2013).
Opens external link in new windowDOI: 10.1007/s00723-012-0425-7

S. Korchak, W. Kilian, L. Mitschang
Degeneracy in cryptophane–xenon complex formation in aqueous solution
Chem. Comm. 51, 1721 (2015).
Opens external link in new windowDOI: 10.1039/C4CC08601E

S. Korchak, W. Kilian, L. Mitschang
Kinetics of Cryptophane-Xenon Complex Formation
Opens external link in new windowProc. Int. Symp. XeMAT 2015, 68 (2015).

S. Korchak, W. Kilian, L. Schröder, L. Mitschang
Design and comparison of exchange spectroscopy approaches to cryptophane–xenon host–guest kinetics
J. Magn. Reson. 265, 139 (2016).
Opens external link in new windowDOI: 10.1016/j.jmr.2016.02.005

To top

Contact

Address

Physikalisch-Technische Bundesanstalt
Abbestraße 2–12
10587 Berlin