Nucl. Med. Biol. Vol. 15, No. I, pp. 31-36, 1988 1x1. J. Radiar. Appl. Instrum. Part B Printed in Great Britain. All rights reserved 0883-2897/88 $3.00 + 0.00 Copyright Q 1988 Pergamon Journals Ltd Considerations Involving Paramagnetic Coordination Compounds as Useful NMR Contrast Agents M. F. TWEEDLE, G. T. GAUGHAN, J. HAGAN, P. W. WEDEKING, P. SIBLEY, LON J. WILSON’ and DANIEL W. LEE’ Squibb Institute of Medical Research, New Brunswick, NJ 08903, U.S.A. and ‘Department of Chemistry, William Marsh Rice University, P.O. Box 1892, Houston, TX 77251, U.S.A. Introduction In this study, various paramagnetic metal chelates of Cr(III), Fe(III), Mn(I1) and Gd(II1) with potential usefulness as NMR contrast agents have been consid- ered and analyzed to determine which chemical char- acteristics govern their effectiveness and biological tolerance. Water exchange rates are examined and correlated with relaxivities. Hydration number is considered. In these regards, special attention has been paid to Gd(II1) species. Previously available proton (H,O) relaxation data for Gd(II1) complexes have not included relaxivity data normalized by experimental values for the number of coordinated water molecules (hydration number). In this work, hydration numbers and rate constants governing the ability of Gd(II1) complexes to enhance the longi- tudinal relaxation time (r,) (at 20 MHz) of water protons have been considered together. From these data, the relative contributions of the inner-sphere and outer-sphere relaxation processes to the observed relaxivities have been estimated. Furthermore, it has been possible to determine experimentally a lower limit for the increase in relaxivity per Gd(III)- coordinated water molecule that is available through manipulation of the rotational correlation time at 20 MHz. LDSo determinations have been made for several free ligands, free metal ions, and metal chelate com- pounds to show the degree to which the safety of metal complexes can be governed by the amount of highly toxic unbound ligand and unbound metal ion contained in injected solutions. Radiolabeled compounds used for radiodetection by TLC and HPLC have been employed to monitor reactions of Gd(II1) chelate compounds with endo- genously available metal ions, and the lS3Gd-labeled chelate compounds have been used to determine biodistribution and pharmacokinetics. Employment of a mouse tumor model, together with knowing the Gd(II1) concentration in tissues, has also allowed the calculation of the relaxivities for various Gd(II1) complexes in a tumor. Results and Discussion Table 1 lists ‘Ok, values (relaxivities determined from T, measurements at 20 MHz) for some metal chelate compounds of interest. Gadolinium(IL1) corn-, plexes have the largest zyxwvutsrqponmlkjihgfedcbaZY ‘Ok, values, as expected from Gd(III)‘s high magnetic moment (a’ = 63 BM*) and symmetric electronic ground state (%). The relax- ation time of protons on water molecules coordinated to a metal ion is on the order of microseconds, while the relaxation time of bulk water protons is on the order of one second. Therefore, the rate at which coordinated water molecules exchange with bulk water, governed by k,, , will be relaxation rate limiting if it is much less than 106s-‘. Chromium(II1) com- pounds are thought to have poor relaxivities because k, is often rate limiting, usually with k,, - 10e6 SK’as exemplified by [Cr(III) (H,O) 6]3 + (Burgess, 1978) while for other Cr(II1) complexes with poly- aminocarboxylic acid ligands, k,, can apparently be enhanced by orders of magnitude (Ogino et al., 1975). In spite of such k,, enhancement, however, [Cr(III)(EDTA) (H,O)J- still exhibits a low relaxivity despite a reasonably high magnetic moment (u2 = 15 Table I. Relaxivities of various metal chelate compounds at 20 MHz and 39”C, 0.1-I mM Compound ‘%, (M-l SK’) (Gd(IIII)(DTPA)(H,O)]‘- 3.7 x 10’ [Gd(III) (DOTA) (H,O) 3.4 x 10’ [Mn(II)(EDTA)(H,O)]*- 2.0 x IO’ ~n(II)(DOTA)]*- I.1 x 10’ [Mn(II)(DTPA)]‘- I.1 x 10’ (Fe(III)(EDTA)(H,O)]- 1.6 x IO’ (Fc(III)(DTPA)]*- 0.7 x IO’ [Fe(IIII)(DOTA)]- 0.4 x 103 [Cr(III)(EDTA)(H,O)]- 0.2 x 10’ 31