%0 Journal Article %A Rudovský, Jakub %A Botta, Mauro %A Hermann, Petr %A Hardcastle, Kenneth I. %A Lukeš, Ivan %A Aime, Silvio %D 2006 %T PAMAM Dendrimeric Conjugates with a Gd−DOTA Phosphinate Derivative and Their Adducts with Polyaminoacids:  The Interplay of Global Motion, Internal Rotation, and Fast Water Exchange %U https://acs.figshare.com/articles/journal_contribution/PAMAM_Dendrimeric_Conjugates_with_a_Gd_DOTA_Phosphinate_Derivative_and_Their_Adducts_with_Polyaminoacids_The_Interplay_of_Global_Motion_Internal_Rotation_and_Fast_Water_Exchange/3070069 %R 10.1021/bc060149l.s001 %2 https://acs.figshare.com/ndownloader/files/4775839 %K correlation time %K water exchange %K Global Motion %K PAMAM Dendrimeric Conjugates %K 298τ Rg %K Gd %K multiparametrical data evaluation %K adduct formation %K dendrimeric conjugates %K relaxivity %K Internal Rotation %K DOTA %K monophosphinated analogue %K G 2 dendrimer %K thiourea linker %K 20 MHz %K 3.1 ns %K 1 H relaxometric data %K 298τ M %K 1 H NMR titration %K water exchange process %K Fast Water ExchangeA series %K conjugate solutions %K 1 H NMRD relaxometric studies %K water residence lifetime %X A series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd−DO3A-PABn complexes (monophosphinated analogue of DOTA) was prepared. The chelates were covalently attached to the G1-, G2-, and G4-PAMAM dendrimers through a thiourea linker in high loads (>90%). The prepared conjugates G1−(Gd−DO3A-PBnN{CS})8, G2−(Gd−DO3A-PBnN{CS})16, and G4−(Gd−DO3A-PBnN{CS})59 showed relaxivities of 10.1, 14.1, and 18.6 s-1 mM-1 at 20 MHz and 37 °C and pH = 7.5, respectively. A variable-pH study (range 2−12) revealed up to 30% increase in the relaxivity at low pH for the G2−(Gd−DO3A-PBnN{CS})16 conjugate. As confirmed by 1H NMR titration of the unmodified G2 dendrimer, this is due to protonation of core tertiary amines leading to a more open and rigid structure. The variable-temperature 17O NMR and 1H NMRD relaxometric studies confirmed that the relaxivity is not controlled by water exchange but by rotational dynamics. A multiparametrical data evaluation using the Lipari−Szabo approach revealed that the water residence lifetime, 298τM, for the conjugates studied was ca. 45−70 ns, which is longer than the value found for the monomeric model compound Gd−DO3A-PABn (16 ns) but short enough so as not to limit the relaxivity. The global rotational correlation time, 298τRg, varied from 1.5 to 3.1 ns and seemed to indicate a sufficiently slow molecular tumbling to achieve the high relaxivities measured; however, the rigidity factor S2 (∼0.26), describing the internal flexibility, was far from optimum. The overall relaxivity was significantly increased (e.g. by a factor of 1.8 for the G1−(Gd−DO3A-PBnN{CS})8 conjugate) when a positively charged polyaminoacid like poly(Arg) or poly(Lys) was added to the conjugate solutions. The electrostatic interactions partially “freeze” the internal mobility of the conjugate and also slow down global motion. This assumption was confirmed by an evaluation of 1H relaxometric data obtained for the G2−(Gd−DO3A-PBnN{CS})16−poly(Lys)59 adduct. Importantly, it was proved that the adduct formation did not hamper the water exchange process. %I ACS Publications