Co^II Complexes as Liposomal CEST Agents

Abstract

Three paramagnetic CoII macrocyclic complexes containing 2‐hydroxypropyl pendant groups, 1,1′,1′′,1′′′‐(1,4,8,11‐tetraazacyclotetradecane‐1,4,8,11‐tetrayl)tetrakis‐ (propan‐2‐ol) ([Co(L1)]2+, 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(propan‐2‐ol) ([Co(L2)]2+), and 1,1′‐(4,11‐dibenzyl‐1,4,8,11‐tetraazacyclotetradecane‐1,8‐diyl)bis(octadecan‐2‐ol) ([Co(L3)]2+) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]2+) forms two isomers as shown by 1H NMR spectroscopy. X‐ray crystallographic studies show one isomer with 1,8‐pendants in cis‐configuration and a second isomer with 1,4‐pendants in trans‐configuration. The [Co(L2)]2+ complex has 1,8‐pendants in a cis‐configuration. Remarkably, the paramagnetic‐induced shift of water 1H NMR resonances in the presence of the [Co(L1)]2+ complex is as large as that observed for one of the most effective LnIII water proton shift agents. Incorporation of [Co(L1)]2+ into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L−1 produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]2+ complex into the liposome bilayer produces a more highly shifted CEST peak at −13 ppm. Taken together, these data demonstrate the feasibility of preparing CoII lipoCEST agents.

Co(ii) complexes of tetraazamacrocycles appended with amide or hydroxypropyl groups as paraCEST agents

“…The 1 H NMR spectrum of [Co(BABC)] 2+ resembles that of the analogous Co( ii ) complex of 1,8-bis(benzyl)-4,11-bis(2-hydroxypropyl)-CYCLAM that contains hydroxypropyl groups instead of amide donor groups in the same cis -pendant configuration. 28 The [Co(HPAM)] 2+ complex shows paramagnetically shifted resonances in the same general region of the spectrum as those of [Co(BABC)] 2+ , consistent with a similar geometry (Fig. 3).…”

“…Hydroxyl OH groups, while promising on Ln(III) complexes, are less promising on Co(II) complexes from the standpoint of the low intensity peaks that are optimized at acidic pH. 23,28 For example, the [Co(THP)] 2+ complex studied here has a k ex for the OH groups of 12 600 s −1 at pH 6.8 (Fig. S13 and S19 †).…”

“…27 However, the Co( ii ) complex of 1,8-bis(benzyl)-4,11-bis-(2-hydroxypropyl)-CYCLAM has the 1,8-pendents in cis -geometry, analogous to [Co(BABC)] 2+ . 28 Comparison of these examples suggests that the bulky benzyl groups promote the formation of the folded cis -I configuration. Selected bond lengths and bond angles can be found in Tables S8 and S11,† respectively.…”

“…In contrast, Co(II) macrocyclic complexes with homochiral hydroxypropyl pendants are rigid and produce relatively sharp ligand proton resonances. 23,24,28 In these complexes, the methyl group of the hydroxypropyl pendant serves to reduce pendant group dynamic processes. However, the CEST peaks attributed to the OH protons of hydroxypropyl are generally not very intense compared to those of amide NH protons.…”

Liposomal MRI probes containing encapsulated or amphiphilic Fe(iii) coordination complexes

“…Our laboratory focuses on the development of transition metal MRI probes, including CEST agents (Fe( ii ), Co( ii ) and Ni( ii )), 13,25 liposomal CEST agents 26 and relaxivity agents such as high-spin Fe( iii ) complexes. 12 The development of Fe( iii ) based agents has many challenges including overcoming low water solubility and lowered relaxivity 12,27–29 and complicated solution chemistry.…”