Synthesis and NMR Studies of New DOTP-like Lanthanide(III) Complexes Containing a Hydrophobic Substituent on One Phosphonate Side Arm Xiaodong Li, † Shanrong Zhang, † Piyu Zhao, † Zoltan Kovacs, † and A. Dean Sherry* ,†,‡ Department of Chemistry, University of Texas at Dallas, Richardson, Texas 75083, and Department of Radiology, Rogers Magnetic Resonance Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, Texas 75290 ReceiVed March 16, 2001 Three derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonic acid) (DOTP) contain- ing a hydrophobic substituent on one side chain were prepared and their lanthanide complexes examined by NMR. The new ligands include 1-(1-octyl-methyl-phosphonic acid)-4,7,10-tris(methylene phosphonic acid)-1,4,7,10- tetraazacyclododecane (C 8 -DOTP), 1-(1-undecyl-methyl-phosphonic acid)-4,7,10-tris(methylene phosphonic acid)- 1,4,7,10-tetraazacyclododecane (C 11 -DOTP), and 1-(1-4-nitro-phenyl-methyl-phosphonic acid)-4,7,10-tris(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane (NO 2 -Ph-DOTP). 1 H NMR spectra of the ytterbium(III) complexes were assigned by using a combination of COSY spectroscopy and a fitting procedure that matches experimental NMR hyperfine shifts with those estimated from a MMX-derived structure. The analysis showed that a single isomer is present in solution and that the bulky hydrophobic substituent occupies the less sterically demanding H 6 equatorial position in the YbL 5- complexes. Although the YbL 5- complexes have lower symmetry due to the added substituent, the average 1 H hyperfine shifts are 5-10% larger in these complexes compared to YbDOTP 5- . This was magnified further in the hyperfine 23 Na NMR shifts of ion-paired sodium ions where the extracellular Na + signal in perfused rat hearts displayed a 28% larger hyperfine shift in the presence of Tm(C 11 -DOTP) 5- than with an equivalent amount of TmDOTP 5- . Introduction The thulium complex of DOTP (Chart 1), TmDOTP 5- , has been widely applied as a hyperfine frequency shift reagent (SR) in resolving the NMR resonances of Na + in extracellular and intracellular compartments. 1,2 The intrinsic negative charge on the complex (HTmDOTP 4- is the predominant anionic species at pH 7.4 3 ) prevents it from crossing cell membranes, and thus the complex forms ion-pair complexes with Na + in all extra- cellular space. Since it was first introduced in the mid-1980s, TmDOTP 5- has been widely used to separate the intra- and extracellular 23 Na resonances from isolated cells, 4-6 perfused organs, 7-14 and intact animals 15-19 by 23 Na NMR. This SR is currently considered the best available for in vivo use even though some of its chemical properties could be improved upon. Notably, TmDOTP 5- forms strong ion pairs with Ca 2+ , Mg 2+ , and other metal cations, 20 and this binding competition not only reduces the efficiency of the SR but also tends to reduce mean arterial blood pressure (∼20%) when infused into laboratory rats. 16 TmDOTP 5- quickly distributes throughout all extra- cellular space and is filtered by the kidneys with a time constant of about 12 min. 18 This relatively short renal clearance time requires that the SR is infused continually throughout a 23 Na NMR study to maintain an adequate shift separation between the intra- and extracellular Na + resonances. * Author to whom correspondence should be sent to either address. Telephone: 972-883-2907 or 214-648-5877. Fax: 972-883-2925 or 214- 648-5881. E-mail: sherry@utdallas.edu or dean.sherry@utsouthwestern.edu. † University of Texas at Dallas. ‡ University of Texas Southwestern Medical Center. (1) Sherry, A. D.; Geraldes, C. F. G. C. Shift Reagents in NMR Spectroscopy. In Lanthanide Probes in Life, Chemical and Earth Sciences: Theory and Practice; Bunzli, J.-C. G., Choppin, G. R., Eds.; Elsevier: Amsterdam, 1989; pp 93-126. (2) Sherry, A. D. J. Alloys Compd. 1997, 249, 153-157. (3) Sherry, A. D.; Ren. J.; Huskens, J.; Brucher, E.; Toth, E.; Geraldes, C. F. C. G.; Castro, M. M. C. A.; Cacheris, W. P. Inorg. Chem. 1996, 35, 4604-4612. (4) Sherry, A. D.; Malloy, C. R.; Jeffrey, F. M. H.; Cacheris, W. P.; Geraldes, C. F. G. C. J. Magn. Reson. 1988, 76, 528-533. (5) Ramasamy, R.; Mota de Freitas, D.; Jones, W.; Wezeman, F.; Labotka, R.; Geraldes, C. F. G. C. Inorg. Chem. 1990, 29, 3979-3985. (6) Wittenkeller, L.; Mota De Freitas, D.; Geraldes, C. F. G. C.; Tome, A. J. R. Inorg. Chem. 1992, 31, 1135-1144. (7) Buster, D. C.; Castro, M. 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