Development of Ln(III) Derivatives as ¹⁹F Parashift Probes

¹⁹F parashift probes with paramagnetically shifted reporter nuclei provide attractive platforms to develop molecular imaging probes. These probes enable ratiometric detection of molecular disease markers using a direct detection technique. Here, we describe a series of trivalent lanthanide (Ln(III)) complexes that are structural analogues of the clinically approved MR contrast agent (CA) ProHance to obtain LnL ¹⁹F parashift probes. We evaluated trans-gadolinium paramagnetic lanthanides compared to diamagnetic YL for ¹⁹F chemical shift and relaxation rate enhancement. The paramagnetic contribution to chemical shift (δ^PCS) for paramagnetic LnL exhibited either shifts to lower frequency (δ^PCS < 0 for TbL, DyL, and HoL) or shifts to higher frequency (δ^PCS > 0 for ErL, TmL, and YbL) compared to YL ¹⁹F spectroscopic signal. Zero-echo time pulse sequences achieved 56-fold sensitivity enhancement for DyL over YL, while developing probe-specific pulse sequences with fast delay times and acquisition times achieved 0.6-fold enhancement in limit of detection for DyL. DyL provides an attractive platform to develop ¹⁹F parashift probes for ratiometric detection of enzymatic activity.