Polymethylated lanthanide 4S4R-M4DOTMA complexes, bearing the ring methyl groups oriented in the SSSS position and the arm methyl groups in the RRRR configuration, exist exclusively as the SAP [Lambda(delta delta delta delta)] isomer in solution throughout the lanthanide series. This observation is in contrast to Ln-8S-M4DOTMA, which was recently reported to adopt the SAP [Lambda(delta delta delta delta)] isomer in the early lanthanides, while the late lanthanides adopt the TSAP [Delta(delta delta delta delta)] isomer. The methyl groups on the ring and the arm are both oriented in the SSSS configuration for Ln-8S-M4DOTMA (Dalton Trans. 2016, 45, 4673-4687, DOI: 10.1039/C5DT03210E). Quantum chemical calculations for Pr- and Yb-4S4R-M4DOTMA indicate that the SAP isomer is significantly more stable. The luminescence profiles of Eu-8S-M4DOTMA and Eu-4S4R-M4DOTMA showed similar profiles signifying identical coordination environments. The hydration state, q, of the Eu(III) complexes was q = 0.910.95, while Tb-8S-M4DOTMA had q = 0.86. A much lower q value was obtained for Tb-4S4R-M4DOTMA (q = 0.67), which indicates an elongation of the Ln-Ow bond. At 400 MHz, the relaxivity of Gd-8S-M4DOTMA is 5.1 +/- 0.1 mM(-1) s(-1) and 3.9 +/- 0.1 mM(-1) s(-1) at 25 and 37 degrees C, respectively, whereas the relaxivity of Gd-4S4R-M4DOTMA is 4.6 +/- 0.1 mM(-1) s(-1) at 25 degrees C and 3.6 +/- 0.1 mM(-1) s(-1) at 37 degrees C. At 45 MHz, the relaxivity of Gd-8S-M4DOTMA is 5.4 +/- 0.1 mM(-1) s(-1), and the relaxivity of Gd-4S4R-M4DOTMA is 4.5 +/- 0.1 mM(-1) s(-1) at 25 degrees C. The temperature dependence of the O-17 NMR transverse relaxation rate of the Gd complexes revealed a 7-fold increase in the bound water residence lifetime of Gd-8S-M4DOTMA (1/k(ex) = tau(M) = 9.0 +/- 0.5 ns and 1/k(ex) = tau(M) = 60 +/- 3 ns). The Pr(III) complex of 8S-M4DOTMA crystallized as TSAP isomer with an apical water. The presence of the apical water for the TSAP of Pr-8S-M4DOTMA was further confirmed with the observation that the fluoride ion replaces the bound water from the TSAP isomer of Pr-8S-M4DOTMA. This was shown by the disappearance of the TSAP peaks and appearance of a new set of less shifted resonances, which exchange with the SAP isomer as confirmed by NMR exchange spectroscopy (EXSY).