Diphosphonate complexes

A series of zinc diphosphonate complexes were synthesized in the presence of diamines of varying chain length. 1-hydroxyethylidenediphosphonate bridges the metal ions with the proto-nated diamine (ethyl-, butyl-, pentyl-, or hexylenediamine) filling in channels or residing between chains. All four structures are different with one-, two-, and three-dimensional networks formed. The coordination number (4-6) and geometry also varies.418... 

Log A values for the analogous EtPO2 complexes are almost identical (Ref. (689)) stability constants for methylene diphosphonate complexes are considerably higher - for Ca2+ log K = 4.7. 

The most advanced along the path to clinical application are the diphosphonate complexes designed as palliative agents for relief of pain... 

Hydroxyapatite particles can be used for radiation synovectomy by exploiting the strong binding of rhenium diphosphonate complexes to the surface of hydroxyapatite (vide supra). The same 186Re-HEDP preparations as for bone palliative therapy are used. When injected into joints, these particles (mean diameter 25 pm, maximum diameter 45 pm) remain within the joint to the extent of at least 95% for several days in arthritic rabbits and rats [156], More recently, microspheres have been labeled with 188Re for this purpose [156a,b],... 

Interesting results were obtained on the temperature dependence of the lifetime of an Eu(III) amino-diphosphonate complex, in H2O and D2O (Holz et al., 1990b). In both solvents, the lifetime decreases as temperature increases and this was ascribed to an additional (photoin-duced) deexcitation pathway due to some ligand energy levels. 

This method is based on the accessibility of the pores in the stationary phase for 99mrpc-iabeled molecules of different molecular sizes. The sample is eluted from a vertical column packed with porous beads of the gel by gravity or low pressure. Smaller Tc species penetrate the pores and are retained on the column, while larger molecules are excluded and are therefore rapidly eluted from the column. This separation technique has particular application for macromolecules, proteins (serum albumin, immunoglobulins [e.g., monoclonal antibodies and their fragments]), but has also been used for separation of small-molecular-weight Tc-diphosphonate complexes. 

Uptake of Tc-PYP in acute myocardial infarction was detected with higher sensitivity than were the known Tc-diphosphonate complexes (Kelly et al. 1979). Using a rat model, the percentage of injected activity per gram of infarct was approximately 2.4 times higher than with Tc-MDP (Davis et al. 1976). Visualization of the infarct can be effected from 24 h-7 days after the onset of symptoms and with maximum sensitivity (96%) between 48 and 72 h (Kelly et al. 1979). 

Kits for the preparation of diphosphonate complexes contain the lyophilized ingredients in a multidose vial. Labeling with Tc-pertechnetate is performed by adding 2-10 ml of sterile Tc eluate by aseptic techniques. When calculating the amount of radioactivity to be added, the labeling efficiency, number of patients, time of injection and radioactive decay must be taken into account. Activities corresponding to 6.6-18.5 GBq... 

Generally, diphopsphonate kits are used for several patient doses, keeping the injected mass of the Tc-diphosphonate complex below 1.0 mg (Castronovo and Callahan 1972). Thus, also in cases, when a single dose is prepared, the standard labeling conditions are applied. 

After intravenous infusion of iron containing drugs or in cases of chronic iron overload in chronic diseases, a change in the bone-to-kidney ratio of diphosphonate complexes has been reported, namely, a decrease in bone uptake and an increase in accumulation in renal parenchyma (McRae et al. 1976). Dissociation of the Tc-diphos-phonate complex and a conversion into the renaltropic gluconate was proved in the presence of ionic iron(II) and calcium. In vivo alteration of the complex was concluded from an increase in renal uptake even after infusion of dextrose. 

Since the stability of " Tc-diphosphonate complexes may be affected, Tc-dipho-sphonates should not be mixed with other drugs or components nor injected simultaneously. 

Diphosphonates form stable Tc(IV) complexes. Contrary to inorganic phosphorus compounds, which are degraded in vivo, the organically bound diphosphonate complexes show high in vivo stability (Davis and Jones 1976). 

Structures of Diphosphonate Complexes. Diphosphonate ligands are widely used to prepare Tc-99m skeletal imaging agents and Tc-99m myocardial infarct imaging agents (1,2). The constitutions, and associated acronyms, of several diphosphonates are shown below along with that of the related ligand pyrophosphate ... 

These structural studies emphasize the central role of polymeric metal-diphosphonate complexes in the chemistry of technetium-diphos-phonate calcium seekii agents. It is clearly the ability of diphosphonates to bridge metal centers that provides the mechanism for the initial sorption of the radiopharmaceutical onto bone. Mixed metal (technetium, tin, and calcium) diphosphonate polymeric complexes are likely to be the dominant chemical species in clinically used skeletal and myocardial infarct imaging events. An understanding of the chemistry of these polymeric species will be crucial to an understanding of the mechanisms of action of diphosphonate radiopharmaceuticals and to the development of more efficacious imaging scents. 

Complexes of the diphosphonic acid (12.125b) with y-ray-emitting isotopes of technetium are useful for medical diagnostic work since they concentrate in the bone. The use of technetium diphosphonate complexes for bone imaging (MRl below) has revolutionised bone-scanning techniques. Technetium pyrophosphate complexes are less satisfactory since the P-O-P linkages are liable to hydrolysis by body enzymes [11,12]. 

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