Accelerating Proton Exchange in 1,8-Bis(dialkylamino)naphthalene Proton Sponges through Intramolecular Catalysis for CEST MRI

Chemical exchange saturation transfer (CEST) MRI generates contrast by transferring saturation from exchangeable protons to bulk water. In diamagnetic agents, labile −NH/–OH protons typically resonate close to water (1–5 ppm), severely limiting selectivity. Thus, larger chemical shift offsets are highly desirable for in vivo applications. Efficient CEST at clinical field strengths also requires exchange rates within a narrow kinetic window. Tetraalkyl 1,8-diaminonaphthalenes (proton sponges) are attractive scaffolds for diaCEST agents because the labile proton locked in a strong hydrogen bond between the two nitrogens in the monoprotonated forms can exhibit extraordinarily large downfield chemical shift offsets from water. However, these compounds do not have CEST because the strong H-bond also results in very slow exchange with the bulk. Here, we report the design, synthesis, and evaluation of a new tetrasubstituted 1,8-diaminonaphthalene derivative in which proton exchange is accelerated by intramolecular catalysis. Detailed structural, thermodynamic, and kinetic studies of 1,8-diaminonaphthalene tetraacetic acid (DANTA) reveal that the carboxylate groups participate in intramolecular hydrogen-bonding interactions with the central N···H+···N bridge, markedly accelerating the proton exchange rate to 492 s–1 at 37 °C, which is within the optimal kinetic regime for CEST at 3 T. Importantly, the carboxylate substituents do not affect the chemical shift offset of the exchanging proton, which remains substantially deshielded and highly downfield shifted at 12.5 ppm from water. In vivo MRI studies further demonstrate that DANTA generates exquisite CEST contrast in the kidneys of mice at 3 T using clinically permissible saturation RF field strengths.