Utilizing a Water-Soluble
Cryptophane with Fast Xenon
Exchange Rates for Picomolar Sensitivity NMR Measurements
- Publication date
- Publisher
Abstract
Hyperpolarized <sup>129</sup>Xe chemical exchange saturation
transfer
(<sup>129</sup>Xe Hyper-CEST) NMR is a powerful technique for the
ultrasensitive, indirect detection of Xe host molecules (e.g., cryptophane-A).
Irradiation at the appropriate Xe-cryptophane resonant radio frequency
results in relaxation of the bound hyperpolarized <sup>129</sup>Xe
and rapid accumulation of depolarized <sup>129</sup>Xe in bulk solution.
The cryptophane effectively “catalyzes” this process
by providing a unique molecular environment for spin depolarization
to occur, while allowing xenon exchange with the bulk solution during
the hyperpolarized lifetime (<i>T</i><sub>1</sub> ≈
1 min). Following this scheme, a triacetic acid cryptophane-A derivative
(TAAC) was indirectly detected at 1.4 picomolar concentration at 320
K in aqueous solution, which is the record for a single-unit xenon
host. To investigate this sensitivity enhancement, the xenon binding
kinetics of TAAC in water was studied by NMR exchange lifetime measurement.
At 297 K, <i>k</i><sub>on</sub> ≈ 1.5 × 10<sup>6</sup> M<sup>–1</sup>s<sup>–1</sup> and <i>k</i><sub>off</sub> = 45 s<sup>–1</sup>, which represent the fastest
Xe association and dissociation rates measured for a high-affinity,
water-soluble xenon host molecule near rt. NMR line width measurements
provided similar exchange rates at rt, which we assign to solvent-Xe
exchange in TAAC. At 320 K, <i>k</i><sub>off</sub> was estimated
to be 1.1 × 10<sup>3</sup> s<sup>–1</sup>. In Hyper-CEST
NMR experiments, the rate of <sup>129</sup>Xe depolarization achieved
by 14 pM TAAC in the presence of radio frequency (RF) pulses was calculated
to be 0.17 μM·s<sup>–1</sup>. On a per cryptophane
basis, this equates to 1.2 × 10<sup>4</sup> <sup>129</sup>Xe
atoms s<sup>–1</sup> (or 4.6 × 10<sup>4</sup> Xe atoms
s<sup>–1</sup>, all Xe isotopes), which is more than an order
of magnitude faster than <i>k</i><sub>off</sub>, the directly
measurable Xe-TAAC exchange rate. This compels us to consider multiple
Xe exchange processes for cryptophane-mediated bulk <sup>129</sup>Xe depolarization, which provide at least 10<sup>7</sup>-fold sensitivity
enhancements over directly detected hyperpolarized <sup>129</sup>Xe
NMR signals