Radiopharmaceutical diphosphonate

Many of the Tc complexes (16, 17, 19) present the 0x0 Tc =0 + core and are pentacoordinate (square pyramid), but other metal oxidation states and coordination numbers are possible, for instance, in (20) (hexacoordinate with the dioxo Tc 02 " core), in (18) (heptacoordinateTc ), in (21) or (23) (hexacoordinate Tc ), or in (22) (hexacoordinate Tc ). In Tc-diphosphonate radiopharmaceuticals, used as bone imaging agents, the metal is beheved to be in the 4-4 oxidation states. The +1 oxidation state in the homoleptic isocyanide complex (22) is expected to be advantageous in terms of the kinetic inertness associated to its low-spin configuration,... 

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. 

Until recently it has rarely been possible to definitively characterize the "mTc species present in a radiopharmaceutical formulation because of the extremely low concentrations involved. In some cases, electrophoresis has been used as a means of determining the minimum number of species present. In a recent example a methylene diphosphonate formulation for preparing a "mTc bone imaging agent was found to produce at least four different "mTc species.581 In favourable circumstances it may be possible to determine the net charge on the ionic materials present by this technique. However, such measurements require careful interpretation if erroneous conclusions are to be avoided, and they provide no detailed information relating to chemical structure.20... 

The proportion of a Tc bone agent which is taken up by bone after intravenous injection will be affected by its binding to proteins in the blood serum. The proportions of the plasma Tc which were protein bound two hours after administration were found to be 16, 31, 54 and 85% with HEDP, MDP, PYP and tripolyphosphate respectively. In addition, the proportion of the administered dose of Tc which was taken up in bone was found to increase linearly with the fraction of Tc in the plasma which was not protein bound. Cox has reported a linear decrease in bone uptake with molecular weight for this series of bone agents, an observation which appears to reflect differences in their plasma protein binding behaviour. Thus the blood serum proteins may compete with bone for the Tc complexes and reduce the bone labelling efficiency of the radiopharmaceutical. The "Tc-diphosphonate formulations showed better performance in this respect than "Tc-PYP or Tc-tripolyphosphate. 

Diphosphonates labelled with " Tc have long been used as radiopharmaceuticals for bone imaging. When labelled with beta emitting isotopes, these agents have the potential for use as therapeutic agents for the treatment of bone metastases. Rhenium-188 labelled HEDP has attractive features as a... 

Various diphosphonates such as MDP, HOP and HEDP labelled with Tc have been investigated for use as bone seeking radiopharmaceuticals. The chemistry of rhenium is similar to that of technetium, and comparative... 

A complete understanding of why specific metal complexes target certain tissues has yet to be achieved, but would be extremely valuable for the rational design of new radiopharmaceuticals. Complexes of 99mTc vvilli diphosphonates, e.g. methylenediphosphonate, localize in bone and especially in areas of disturbance of bone metabolism, such as tumours thus they may be used to map the presence and location of bony metastases from various types of cancer. Chelates such as "Tc-DTPA may be used to study differential renal function in the kidneys or to monitor the function of a transplanted kidney. Attachment of chelating groups, often based on DTPA, to antibody proteins permits the formation of Tc- or in-labelled antibodies for tumour localization. 

International Commission on Radiological Protection (1987b) Technetium-labelled erythrocytes. In Annals of the ICRP, radiation dose to patients from radiopharmaceuticals, biokinetic models and data. ICRP publication 53, vol 18, no 1-4. Pergamon, Oxford, pp 209-210 International Commission on Radiological Protection (1991) Technetium-labelled denatured erythrocytes. In Annals of the ICRP, radiological protection in biomedical research. ICRP publication 62, vol 22, no 3. Pergamon, Oxford, pp 25-28 Kelly RJ, Chilton HM, Hackshaw BT, Ball JD, Watson NE, Kahl FR, Cowan RJ (1979) Comparison of Tc-99m pyrophosphate and Tc-99m methylene diphosphonate in acute myocardial infarction concise communication. J Nucl Med 20 402-406... 

Srivastava SC, Meinken G, Smith TD, Richards P (1977) Problems associated with stannous " Tc-radiopharmaceuticals. Int J Appl Radial Isot 28 83-95 Subramanian G, McAfee JG, Bell EG, Blair RJ, Mara RE, Relston PH (1972) " Tc-labeled polyphosphates as skeletal imaging agent. Radiology 102 701-704 Subramanian G, McAfee JG, Blair RJ, Kallfelz FA, Thomas ED (1975) Technetium-99m methylene diphosphonate - a superior agent for skeletal imaging comparison with other technetium complexes. J Nucl Med 16 744-755... 

Bevan JA, Tofe AJ, Benedict JJ, Francis MD, Barnett BL (1980) Tc-99m HMDP (hydroxymethylene diphosphonate) a radiopharmaceutical for skeletal and acute myocardial infarct imaging. I. Synthesis and distribution in animals. J Nucl Med 21 961-966 Buell U, Kleinhans E, Zorn-Bopp E, Reuschel W, Muenzing W, Moser EA, Seiderer M (1982) A comparison of bone imaging with Tc-99m DPD and Tc-99m MDP concise communication. J Nucl Med 23 214-217... 

Tc radiolabelled diphosphonate is injected intravenously and is rapidly absorbed into the extracellular fluid. Although the exact mechanism of uptake of the radiopharmaceutical from the extracellular fluid into the bone is not completely understood, it is thought that both the osteoblastic activity and vascularity of the bone have roles. Following uptake the radiopharmaceutical is then adsorbed onto the surface of the inorganic crystalline bone matrix. A few hours post injection the blood level is approximately 3.5% of the injected dose and bone uptake is at 50% of the injected dose (Thrall and ZiESSMAN 2001 Haasbeek and Green 1994). 

The most common radiopharmaceutical in clinical use for skeletal imaging is diphosphonate labelled... 

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