Metalloradiopharmaceuticals in Nuclear Medicine

Radiopharmaceuticals are drugs containing a radionuclide and are used routinely in nuclear medicine for the diagnosis or therapy of various diseases. They are mostly small organic or inorganic compounds, but can also be macromolecules such as monoclonal antibodies or their fragments labeled with a radionuclide. Those agents whose biodistribution is determined by biological interaction, e. g. receptor binding, are termed target-specific radiopharmaceuticals.

For diagnostic imaging agents, technetium-99m is frequently the radionuclide of choice because it has optimal nuclide properties (half-life of 6h and appropriate Gamma-energy of 140 keV). The inconvenience of purchasing a short-lived radionuclide was overcome by the development of the ⁹⁹Mo/^99mTc generator, which is based on transient equilibrium between the parent radionuclide ⁹⁹Mo (66h half-life) and the daughter radionuclide ^99mTc (6h half-life). The generator makes this radionuclide both routinely available and economical. Finally, the ^99mTc-radiopharmaceutical can easily be prepared in the clinic by means of prefabricated kits. So it is no surprise that more than 90% of routine in vivo imaging is performed with technetium-99m [1,2].

Table 1. Metal nuclides for diagnostic or therapeutic application

Beside technetium, many other radiometals have been or are being investigated for their uses in nuclear medicine [3]. This comprises not only radiometal-labeled agents used in gamma scintigraphy and positron emission tomography (PET), but also beta and alpha emitters for radionuclide therapy [4] (Table 1).
The development of effective metalloradiopharmaceuticals is a complex task which is not simply accomplished by attaching a radionuclide to a nonradiolabeled targeting vector (Fig.1).

Fig.1. Schematic representation of the bifunctional approach as a strategy of radiopharmaceutical design

Because of the unphysiological nature of the radiometal, the structure of the biomolecule where the chelate is appended, will be altered and the biodistribution will change drastically. The search for metalloradiopharmaceuticals involves therefore chelate systems that stable bind the radiometal, and, since it will be directly involved in optimizing the biochemical properties of the radiopharmaceutical, it has to be compatible in structure and physicochemical properties. In recent years, new chelate systems have been developed (Fig.2) for binding technetium (as well its congener rhenium) at oxidation states V, III, and I involving metallnitrido cores (1) [5], mixed-ligand complexes (2) [6] and metal-tricarbonyl derived complexes (3) [7,8].