Since different cages with distinct 129Xe chemical shifts and different binding moieties can be used concurrently, the simultaneous see more recognition of different target molecules, i.e. multiplexing, is possible [94] and [107]. The scheme described above allows for MRI detection of (multiple) immobilized biosensors bound to targets present in a stationary matrix. Since the hp 129Xe can be delivered in excess, biosensor detection

in the micro-molar regime is possible. The sensitivity can be significantly increased further through an indirect detection method developed by Pines and co-workers [108]. HYPER-CEST is a combination of CEST (chemical exchange saturation transfer) with hp 129Xe and is reminiscent of the concept described for XTC above. Chemical shift selective irradiation at the 129Xe frequency of the bound xenon is applied to destroy the hyperpolarized state. Chemical exchange between bound

xenon and xenon in the bulk solution (for instance blood) then leads to a depletion of the bulk solution hp 129Xe signal as long as the irradiation is applied. The signal reduction is indicative of the biosensor presence and therefore of the target molecule. Because the 129Xe signal arising from the bulk solution is much stronger than that from the bound xenon, and because the depletion can be ‘accumulated’ over time, HYPER-CEST allows for nano-molar sensitivity. The technique requires however, that the hp 129Xe polarization level in the solution does not significantly fluctuate due to other causes. Additional ways to boost sensitivity for xenon-biosensors are in the usage of dendrimer–cryptophane supramolecular INCB018424 molecular weight constructs [109] and viral capsid scaffolds [110] that both increase the number of cages per target molecule. Further, functionalized zeolite nano-particles have also been explored as potential biosensors [111]. The advantage of these particles is that

they may accommodate a copious amount of xenon atoms leading to a stronger directly detected signal. The concept of gas MRI can be extended by a remote detection scheme developed by Pines and co-workers [112] where the excitation coil and pulsed magnetic field gradient coils are completely separated in space from the Thalidomide detection coil. In this scheme, hp 129Xe is delivered to the sample region where the excitation and encoding take place. The hp 129Xe is then transferred to a distant detection region where the encoded information is read out with a higher sensitivity than what would be possible in the sample region. In its most basic form, this scheme does not have a direct dimension (such as frequency encoding) and requires point-by-point measurement of the encoded phase for all dimensions. The long hp 129Xe T1 relaxation facilitates the experiments as the encoded information is stored as “magnetization”, despite the 50% signal loss associated with the use of a storage pulse analogue to that in stimulated echo sequences.