Leif Schröder's Lab

About the lab

Our group works on the development of novel magnetic resonance reporters and the related detection techniques for diagnostic imaging and spectroscopy. Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular diagnostics.
The research in our lab uses the Hyper-CEST method as an ultra-sensitive technique in xenon MRI to combine the advantages of non-invasive imaging with the high sensitivity of hyperpolarized xenon and the specificity of functionalized reporters.

Featured research (8)

A serious limitation of high resolution 129Xe chemical exchange saturation transfer (CEST) NMR spectroscopy for comparing competitive host-guest interactions from different samples is the long acquisition time due to step-wise encoding of the chemical shift dimension. A method of optimized use of 129Xe spin magnetization to enable the accelerated and simultaneous acquisition of CEST spectra from multiple samples or regions in a setup is described. The method is applied to investigate the host-guest system of commercially available cucurbit[7]uril (CB7) and xenon with competing guests: cis-1,4-bis(aminomethyl)cyclohexane, cadaverine, and putrescine. Interactions with the different guests prove that the observed CEST signal is from a CB6 impurity and that CB7 itself does not produce a CEST signal. Instead, rapid interactions between xenon and CB7 manifest in the spectrum as a broad saturation response that could be suppressed by cis-1,4-bis(aminomethyl)cyclohexane. This guest prevents interactions at the CB7 portals. The suggested method represents a type of spectroscopic imaging that is capable of capturing the exchange kinetics information of systems that otherwise suffer from shortened T2 times and yields multiple spectra for comparing exchange conditions with a reduction of >95% in acquisition time. The spectral quality is sufficient to perform quantitative analysis and quantifications relative to a CB6 standard as well as relative to a known blocker concentration (putrescine) that both reveal an unexpectedly high CB6 impurity of ca. 8%.
Xenon magnetic resonance imaging (MRI) provides excellent sensitivity through the combination of spin hyperpolarization and chemical exchange saturation transfer (CEST). To this end, molecular hosts such as cryptophane-A or cucurbit[n]urils provide unique opportunities to design switchable MRI reporters. The concentration determination of such xenon binding sites in samples of unknown dilution remains, however, challenging. Contrary to 1H CEST agents, an internal reference of a certain host (in this case, cryptophane-A) at micromolar concentration is already sufficient to resolve the entire exchange kinetics information, including an unknown host concentration and the xenon spin exchange rate. Fast echo planar imaging (EPI)-based Hyper-CEST MRI in combination with Bloch–McConnell analysis thus allows quantitative insights to compare the performance of different emerging ultra-sensitive MRI reporters.
Spin exchange between different chemical environments is an important observable for characterizing chemical exchange kinetics in various contexts, including protein folding, chelation chemistry, and host-guest interactions. Such spins experience effective spin-spin relaxation rate, R 2,eff , that typically shows a dispersive behavior which requires detailed analysis. Here, we describe a class of highly simplified R 2,eff behavior by relying on hyperpolarized 129 Xe as a freely exchanging lig-and reporter. It provides large chemical shift separations that yield reduced expressions of both the Swift-Connick and the Carver-Richards treatment of exchange-induced relaxation. Despite observing a diamagnetic system, R 2,eff is dominated by large Larmor frequency jumps and thus allows detection of otherwise inaccessible analyte concentrations with a single spin echo train (only 0.01 % of the overall hyperpolarized spins need to be transiently bound to the molecule). The two Xe hosts cryptophane-A monoacid (CrA-ma) and cucurbit[6]uril (CB6) represent two exemplary families of container molecules (the latter one also serving as drug delivery vehicles) that act as highly efficient phase shifters for which we observed unprecedented exchange-induced relaxivity, r 2 (up to 866 s −1 mM −1). By including methods of spatial encoding, multiple data points can be collected simultaneously to isolate the exchange contribution and determine the effective exchange rate in partially occupied binding sites with a single delivery of hyperpolarized nuclei. The relaxivity is directly related to the guest turnover in these systems and temperature-dependent measurements yield an activation energy of E A = 41 kJ/mol for Xe@CrA-ma from simple relax-ometry analysis. The concept is transferable to many applications where Xe is known to exhibit large chemical shifts.
Hyperpolarized noble gases have been used early on in applications for sensitivity enhanced NMR. 129 Xe has been explored for various applications because it can be used beyond the gas-driven examination of void spaces. Its solubility in aqueous solutions and its affinity for hydrophobic binding pockets allows "functionalization" through combination with host structures that bind one or multiple gas atoms. Moreover, the transient nature of gas binding in such hosts allows the combination with another signal enhancement technique, namely chemical exchange saturation transfer (CEST). Different systems have been investigated for implementing various types of so-called Xe biosensors where the gas binds to a targeted host to address molecular markers or to sense biophysical parameters. This review summarizes developments in biosensor design and synthesis for achieving molecular sensing with NMR at unprecedented sensitivity. Aspects regarding Xe exchange kinetics and chemical engineering of various classes of hosts for an efficient build-up of the CEST effect will also be discussed as well as the cavity design of host molecules to identify a pool of bound Xe. The concept is presented in the broader context of reporter design with insights from other modalities that are helpful for advancing the field of Xe biosensors.

Lab head

Leif Schröder
  • Division of Translational Molecular Imaging
About Leif Schröder
  • Our group works on the development of magnetic resonance detection techniques for novel targeted contrast agents. Xenon biosensors have an outstanding potential to increase the significance of magnetic resonance imaging (MRI) in molecular imaging and to combine the advantages of MRI with the high sensitivity of hyperpolarized xenon and the specificity of a functionalized contrast agent.

Members (4)

Lars - Winkler
  • Leibniz-ForschungsInstitut für Molekulare Pharmakologie
Patrick Schuenke
  • Physikalisch-Technische Bundesanstalt
Jan Oliver Jost
  • Leibniz-ForschungsInstitut für Molekulare Pharmakologie
Patrick Werner
  • German Cancer Research Center

Alumni (6)

Christopher Witte
  • Leibniz-ForschungsInstitut für Molekulare Pharmakologie
Honor May Rose
  • Leibniz-ForschungsInstitut für Molekulare Pharmakologie
Federica Rossella
Matthias Schnurr
  • Leibniz-ForschungsInstitut für Molekulare Pharmakologie