Magnetic dipolar interactions between solvent water protons and paramagnetic solutes, such as chelated Gd3 ions, provide an efficient means for increasing both the longitudinal (1/T1) and transverse (1/T2) relaxation rates of solvent protons. For small paramagnetic chelate complexes, interactions by direct water coordination to the metal ion (inner sphere) and diffusion in the outer sphere environment of the metal complexes are the two main contributors to relaxation enhancement. At magnetic resonance imaging (MRI) fields and physiologic conditions, these contributions are additive and generally comparable in magnitude, whereas for macromolecular complexes, inner sphere contributions tend to dominate relaxation. The inner sphere contribution to 1/T1 is given by: 1/T1p q[Gd3 ]/55.5(T1M M). Here, q is the number of coordinated inner sphere water molecules, T1M is the longitudinal relaxation time of the coordinated water protons, and M is their lifetime on the metal ion. For coordinated Gd3 ions with q 1, both T1M and M are of the order of microseconds. 1/T1 is a complicated function of the strength of the interaction, the magnitude of the applied MRI field B0, and an overall correlation time, C. C is given by C 1 R 1 S 1 M 1, the inverse of the sums of the reciprocals of the orientational relaxation time of the complex R, the electronic relaxation time of the paramagnetic metal ion S, and M, respectively. For Gd3 ions, S can also be a function of B0, often characterizable by another correlation time V. In any event, the enhancement is maximized for kinetically labile complexes, when exchange of the inner sphere water is rapid (but not too rapid), such that C M T1M (1–3). Attachment of Gd3 chelates to macromolecules generally leads to a peak in 1/T1 in the MRI field range (2,3). This phenomenon is well understood and is associated with the long R of macromolecular complexes and related to the fact that S becomes very long at MRI fields. Hence, formation of a rigid macromolecular paramagnetic complex is a design goal for obtaining high-relaxivity contrast agents. To date, several covalently bonded Gd3 macromolecular complexes have been explored, but the peak relaxivity has been limited either by lack of rigidity or by a long value of M (4–8). Relatively rigid paramagnetic macromolecular complexes have been generated in vivo, in the blood pool, through reversible noncovalent hydrophobic interactions of small lipophilic Gd3 chelates with serum (9,10). Depending on the specifics of the docking interaction at the known hydrophobic patches on albumin, highly efficient intravascular contrast agents can be produced. In addition, the reversibility of the noncovalent interactions ensures increased circulation lifetime of the agent and ease of elimination by the kidneys as small molecules, thereby reducing toxicity problems. A monomeric nonaromatic MR agent (code-named MP-2269) that binds to serum albumin has been synthesized. MP-2269 is the Gd3 complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-L-aspartyl-lysine-derived-DTPA (see Fig 1 for MP-2269 structure). The lysine-DTPA derivative is -(N,N-bis-[2-[N ,N -bis(carboxy-methyl-amino)]]ethyl)-L-lysine (11). The hydrophobic pentylbicyclo[2.2.2]octane side chains associate with albumin, and negAcad Radiol 2002; 9(suppl 1):S11–S16
