Indium transferrin

In spite of its larger size, with an ionic radius of 0.80A (161), In3+ appears to bind to transferrin with an affinity close to that of Fe3+ (145). In3+ displaces Cu2+ from copper-saturated ovotransferrin, and the In3+ even remains bound in the presence of an added twofold excess of Fe3+. Indium-transferrin also migrates indistinguishably from iron-transferrin (145) and gives the same closed conformation, as judged by small-angle X-ray scattering (105). 

The major uses of lndlum-111 in medicine are listed in Table 2. Indium-111 labeled DTPA is the preferred agent for the study of cerebral spinal fluid kinetics (cisternography)( ). Indium-labeled bleomycin has been used for tumor scanning C2.), although citrate has achieved greater clinical use. It appears that indium bleomycin is in fact a weak chelate and the in vivo distribution is very similar to that of indium transferrin. 

A further prerequisite for an indium complex to be useful for nuclear medicine applications is that it be resistant to exchange with the plasma protein transferrin. Indium binds to transferrin at the Fe binding site with a stability constant (/f ) of lO in the presence of bicarbonate [7]. The formation constants of indium with ethylenediaminetetraacetic acid (EDTA) (log = 25.0) and DTPA (log Ki = 29.0) are such that at infinite dilution equilibrium would favor the formation of indium transferrin [8J. The slow dissociation of indium from these complexes hinders the formation of indium transferrin. 

The similarities between Ga, In and Fe " are manifest in vivo by the binding of all three ions to the serum protein transferrin, Tf, normally used for iron transpQit. The formation constant for the Ga -Tf complex has been found to be and Welch has calculated values for the equilibrium constants for the exchange of trivalent metal ions between EDTA or DTPA and Tf as shown in Table 19. These figures show that only the DTPA complex of Ga is stable with respect to metal exchange with Tf. Table 19 also shows values for the equilibrium exchange reaction between Tf and hydroxide ion. These indicate that, while the indium-Tf complex should be stable to hydrolysis in vivo, in the long term the insoluble Ga(OH)3 should form from the... 

Hosain E, McIntyre PA, Poulose K, Stern HS and Wagner NH (1969) Binding of trace amounts of ionic indium-113m to plasma transferrin. Clin Chim Acta 24 69-75. 

Another way to slow substitution is to covalently bond a ligand to silica— compare bonding ligands to monoclonal antibodies above. Oxine bound to silica reacts much more slowly with Al, for example, than when it is in solution. Another example of slow substitution at Al is related to the indium chemistry mentioned above, involving its slow transfer from its transferrin complex by reaction with iron(III)-citrate to form the much more stable combination of iron-transferrin and aluminum-citrate complexes. Further examples of slow substitution kinetics involving ferritin will be found in the iron(III) section (Section 8.3.4). 

Initial work on radiolabeling of autologous polymorphonuclear leukocytes was performed by McAfee and Thakur [30]. One of the compounds they examined was the nonpolar, lipid-soluble complex 8-hydroxyquinoline (oxine) (Fig. 2). Indium forms a neutral, lipid-soluble complex with oxine which will penetrate cellular membranes. Subsequently, studies showed that this technique could be used to label leukocytes and platelets with retention of biological activity [31]. After diffusing intracellularly, the ln-oxine complex dissociates and the " In is bound to nuclear and cytoplasmic proteins (Fig. 3) [32-34]. Due to the high stability of indium with the blood protein transferrin, it is necessary to label platelets or WBCs in the absence of plasma. In addition, a final wash of the labeled cells using plasma will remove any loosely bound indium by complexation with transferrin [35,36]. 

However, while thermodynamic stability issues decide the direction in which the transfer of the radiometal occurs, of greater practical importance is the kinetic stability which determines the rate at which it happens. Studies have shovm that indium does in fact transfer from antibody-DTPA conjugates to transferrin in vivo, but that this occurs at a rate of only about 10% per day which is considered to be too slow to radically influence the quality of the images obtained. The feet that onty a slow rate of dissociation is observed even when one of the carboxylic acid groups is employed for conjugation is explained by the fact that indium requires only seven atoms to complete its co-ordination. This is not the case for other radiometals such as yttrium which are discussed below. 

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