Skeletal imaging agents

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

In summary, substitution routes have the potential of introducing hitherto unattainable flexibility and subtlety into the preparation of technetium radiopharmaceuticals. As currently being developed, these routes should lead to new classes of technetium radiopharmaceuticals, the properties of which will be considerably different and more easily controlled than those of complexes prepared by the standard Sn(n) reduction of pertechnetate. 

Because of the nascent state of technetium chemistry, considerable emphasis is currently being given to the characterization of technetium complexes by single crystal x-ray structure analysis. These analyses provide a firm foundation upon which subsequent development and elaboration of technetium chemistry may be based. Approximately twenty technetium complexes have been characterized by single crystal x-ray methods (p, and several of the resulting structures have considerable relevance to radiopharmaceutical development. 

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Gentisic acid a new stabilizer for low tin skeletal imaging agents concise communication. J Nucl Med 21 366-370... 

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... 

Schwarz A, Kloss G (1981) Technetium-99m DPD - a new skeletal imaging agent. J Nucl Med 22(Abstr) 7... 

Tofe AJ, Bevan JA, Fawzi MB, Francis MD, Silberstein EB, Alexander GA, Gunderson DE, Blair K (1980) Gentisic acid a new stabilizer for low tin skeletal imaging agents concise commimica-tion. J Nucl Med 21 366-370... 

United States Pharmacopeial Convention (2005) Official Monographs USP 28, technetium Tc-99m succimer injection. United States Pharmacopeia (USP) 28-national formulary (NF) 23, p 1864 Van Duzee BF, Bugaj JE (1981) The effect of total technetium concentration on the performance of a skeletal imaging agent. Clin Nucl Med 6(Suppl) 148 Westera G, Gadze A, Horst W (1985) A conveimient method for the preparation of " Tc(V)-DMSA. Int J Appl Radiat Isot 36 311-312... 

Van Duzee BF, Bugaj JE (1981) The effect of total technetium concentration on the performance of a skeletal imaging agent. Clin Nucl Med 6(Suppl) P148... 

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 ... 

The development of the instant radiopharmaceutical kit in the 1970s was followed by the development of technetium imaging agents for renal, skeletal, and hepatobiliary imaging. At that time, the coordination chemistry of technetium was not well understood and as a result, the early radiopharmaceuticals are not fully characterized. Studies of the coordination chemistry of technetium intensified in the late 1970s leading to the discovery of Tc brain, heart, and renal agents. These... 

Subramanian G, McAfee JG, Blair RG, Kallfelz FA, Thomas FD (1975) Technetium-99m-methylene-diphosphonate - a superior agent for skeletal imaging comparison with other technetium complexes. J Nucl Med 16 744-755... 

Conklin JJ, Alderson PO, Zizic TM et al (1983) Comparison of bone scan and radiograph sensitivity in the detection of steroid-induced ischemic necrosis of bones. Radiology 147 221-226 Council of Europe (2005) Technetium " Tc medronate injection. In European Pharmacopeia 5.0, monograph no 641. Council of Europe, Maisonneuve, Sainte-Ruffine, p 1219 Davis MA, Jones AG (1976) Comparison of " Tc-labeled phosphate and phosphonate agents for skeletal imaging. Semin Nucl Med 6 19-31... 

Djokiffi et al. have investigated yttrium-90-labeling of the 2,3-dicarbox-ypropane-l,l-diphosphonic acid (DPD), which is currently labeled with technetium-99m and as a Tc DPD clinically used as bone imaging agent. With high skeletal uptake, a minimum uptake in soft tissues and rapid blood clearance, the Y-DPD complex proved to be an excellent candidate for targeting tumor therapy. 

For common preclinical laboratory specimens such as mouse and rat, it is possible to image the skeletal features associated with different developmental stages of serial end-point harvested specimens (Fig. 1). Additionally, with the use of radio-opaque contrast agents, it is possible to image capture the soft tissue features of these specimens (Fig. 2). The combined imaging can be used to illustrate various anatomical features of interest within the same specimen (Fig. 3). This imaging technique therefore has an added potential of conferring multi-modality to an individual micro-CT machine. 

Figure 3. Membrane skeletal association of FPR. Neutrophils were solubilized with Triton X-100 and the extracts were spun over sucrose density gradients. The distribution of photoaffinity labeled FPR was analyzed on SDS-polyacrylamide gels with a Phosphor Imager. Percent receptors that are coupled to the membrane skeleton are shown for responsive control cells (C), partially (PD) and fully (FD) desensitized neutrophils. In addition, values are shown for cells after solubilization in the presence of agents causing depolymerizaiton of actin filaments, like KCl, p-chloromercuriphenylsulfonic acid (pCMPS) or DNAse I. For experimental details see [44].

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. 

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