Encapsulation of xenon by bridged resorcinarene cages with high ¹²⁹Xe NMR chemical shift and efficient exchange dynamics

Functionalized cages encapsulating xenon atoms enable highly sensitive, background-free molecular imaging through a technique known as HyperCEST ¹²⁹Xe MRI. Here, we introduce a class of potential biosensor cage structures based on two resorcinarene macrocycles bridged either by aliphatic carbon chains or piperazines. First-principles-based modeling predicts a high chemical shift (about 345 ppm) outside the typical experimental observation window for ¹²⁹Xe encapsulated by the aliphatically bridged cage and two ¹²⁹Xe resonances for the piperazine-bridged cages corresponding to single and double loading. Based on the computational predictions as well as ¹²⁹Xe chemical exchange saturation transfer (CEST) and T₂ relaxation nuclear magnetic resonance experiments, we confirm Xe encapsulation in the aliphatically bridged and double encapsulation in the piperazine-bridged resorcinarene in methanol. The cages show fast Xe exchange rates (12,000–49,000 s⁻¹), resulting in a high CEST response regardless of the relatively low binding constant (0.09–3 M⁻¹).