117017-02-4Relevant academic research and scientific papers
Synthesis and characterization of pH-sensitive, biotinylated MRI contrast agents and their conjugates with avidin
Vibhute, Sandip M.,Engelmann, Joern,Verbic, Tatjana,Maier, Martin E.,Logothetis, Nikos K.,Angelovski, Goran
, p. 1294 - 1305 (2013/05/09)
Responsive or smart contrast agents (SCAs) provide new opportunities in magnetic resonance imaging (MRI) to examine a number of physiological and pathological events. However, their application in vivo remains challenging. Therefore, much research is focused on the optimization of their properties, to enable their use in additional imaging modalities, pre-targeted delivery, or to increase the local concentration of the agent. The key feature in the SCA synthetic modification is the retention of their physicochemical properties related to the specific MR response. Here, we report the preparation and characterization of pH sensitive SCAs appended with a phosphonate pendant arm and either an aliphatic (GdL1) or aromatic linker (GdL2). The longitudinal relaxivity of GdL1 and GdL2 increases by 146% and 31%, respectively, while the pH decreases from 9 to 5. These two SCAs were converted to the biotinylated systems GdL3 and GdL4 and their interaction with avidin was investigated. The binding affinity with avidin was assessed with a fluorescence displacement assay and with MRI phantom experiments in a 3T MRI scanner. The fluorometric assay and MRI E-titrations revealed a 3:1 binding mode of GdL3-4 to avidin with the binding affinity as high as that of the parent avidin-biotin complex. The high binding affinity was confirmed with MRI by a competitive assay. The avidin-GdL 3-4 complexes thus obtained exhibit changes in both r1 and r2 that are pH dependent. The results reveal a new pathway for the modification and improvement of SCAs to make them more suitable for in vivo application.
Synthesis of a novel 'smart' bifunctional chelating agent 1-(2-[β,d-galactopyranosyloxy]ethyl)-7-(1-carboxy-3-[4-aminophenyl]propyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (Gal-PA-DO3A-NH2) and its Gd(III) complex
Wardle, Nick J.,Herlihy, Amy H.,So, Po-Wah,Bell, Jimmy D.,Bligh, S.W. Annie
, p. 4714 - 4721 (2008/03/13)
A new synthetic pathway to 1-(2-[β,d-galactopyranosyloxy]ethyl)-7-(1-carboxy-3-[4-aminophenyl]propyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (Gal-PA-DO3A-NH2) and 1-(2-[β,d-galactopyranosyloxy]ethyl)-4,7,10-tris(carboxymethyl)-1, 4,7,10-tetraazacyclododecane (Gal-DO3A) chelating agents was developed involving full hydroxyl- and carboxyl-group protection in precursors to product. Two sequences of cyclen-N-functionalisation were subsequently investigated, one successfully, towards synthesis of the novel 'smart' bifunctional Gal-PA-DO3A-NH2 chelate. The longitudinal proton relaxivities of the neutral [Gd-(Gal-PA-DO3A-NH2)] and [Gd-(Gal-DO3A)] complexes were increased by 28% and 37% in the presence of β-galactosidase, respectively.
Unexpected Selectivity in the Alkylation of Polyazamacrocycles
Kruper, William J.,Rudolf, Philip R.,Langhoff, Charles A.
, p. 3869 - 3876 (2007/10/02)
Reaction of equivalent amounts of free base polyazamacrocycles with an alkyl halide in a nonpolar, aprotic solvent affords the mono-N-alkylation product as its monohydrohalide salt in high yield with excellent selectivity.This unexpected selectivity has been explained in terms of the high affinity of the alkylated product for a single proton which attenuates the nucleophilicity of the remaining nitrogen atoms.Selectivity is dependent upon a number of factors including macrocycle ring size, solvent polarity, and the steric nature of the electrophile.The approach has been allowed for a short, convergent route to bifunctional lanthanide chelators which are useful in therapeutic applications.
