ReviewNew directions in the coordination chemistry of 99mTc: a reflection on technetium core structures and a strategy for new chelate design
Introduction
The ability to incorporate readily available radionuclides with optimal decay characteristics into tracer molecules has been the foremost consideration in developing diagnostic radiopharmaceuticals. In this respect, 99mTc has become the mainstay of diagnostic nuclear medicine and in some chemical form is used in the majority of the diagnostic scans performed each year in hospitals [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. This preferential use of 99mTc radiopharmaceuticals reflects the ideal nuclear properties of the isotope, as well as its convenient availability from commercial generator columns. 99mTc emits a 140-keV γ-ray with 89% abundance, which is close to optimal for imaging with commercial gamma cameras. The absence of tissue-damaging corpuscular radiation allows the injection of activities of more than 30 mCi with low radiation exposure to the patient [8]. The 6-h half-life is sufficiently long for pharmaceutical preparation and in vivo accumulation in the target tissue, but yet short enough to minimize radiation dose to the patient or to cause environmental repercussions. Moreover, the availability of the relatively stable 99Tc isomer allows development of technetium coordination chemistry and modeling of technetium radiopharmaceuticals [21], [22], [23], [24], [25].
However, one disadvantage of technetium chemistry is that the metal, unlike 123I or 18F, cannot directly substitute a hydrogen atom of a biomolecule, nor can other common constituents of biomolecules, such as carbon, nitrogen or oxygen, be replaced by technetium. Consequently, the design of imaging agents in general requires considerable development of the coordination chemistry of the radiometal.
Section snippets
General types of technetium radiopharmaceuticals
Technetium-based radiopharmaceuticals can be described using various criteria related to either the relevance of the technetium complexation to the overall fate of the complex (technetium-essential or technetium-tagged). Conceptually, for Tc-essential, the Tc atom completes the vector. In the case of Tc-tagged, the Tc atom rides the vector. In the case of the technetium-essential compounds, technetium imparts a particular physicochemical character to the molecule, which effectively enhances or
The coordination chemistry of technetium in the development of radiopharmaceuticals
It is noteworthy that all formal oxidation states of technetium between −I and +VII are represented by characterized compounds [57]. The most stable and readily accessible oxidation states are often characterized by chemically robust core structures, which may be exploited as platforms for the development of radiopharmaceutical reagents. Several examples of structures incorporating such core geometries are illustrated in Fig. 2. The {MO}3+ core, characteristic of Tc(V), is stabilized by
MAG3-based and related bifunctional chelates [36,107,108]
The 99mTc(V)O complex of mercaptoacetyltriglycine (MAG3H5), [TcO(MAG3H)]− shown in Fig. 8 was developed by Fritzberg et al. [109] as an anionic kidney-imaging agent. The parent ligand is readily derivatized as the S-acetyl MAG3-ethyl ester, containing a p-isothiocyanatobenzyl substituent, or as the S-acetyl MAG3-hydroxysuccinimidyl ester for conjugation to biomolecules [110].
MAG3H5 is a member of the general family of NxS(4−x) chelates, which are employed for coordination to the {Tc(V)O}3+ core
The 99mTc/HYNIC system
An alternative pendant approach to radiolabeling is provided by HYNIC [119], [120], [121], [122], [123], [124], [125]. When combined with a molecule such as a protein, polypeptide or glycoprotein in neutral or slightly basic media, the protein-reactive part of HYNIC reacts with nucleophilic groups in the macromolecule, such as the ɛ-amine groups of lysine residues, to yield a conjugate containing free hydrazine/hydrazide groups, referred to as HYNIC-protein. Since we first reported the use of
Single amino acid chelators for the {Tc(I)(CO)3}1+ core
While the {Tc(V)O}3+ and the various Tc-organohydrazino cores are the most extensively studied technetium subunits for radiopharmaceutical development, other core geometries allow the introduction of a variety of novel chelators, which may influence biodistribution, sample purity and stability of the preparation. In this respect, the organometallic nature of the Tc-tricarbonyl core has brought renewed interest in the design of 99mTc radiopharmaceuticals. The Tc(I)-tricarbonyl core offers a
Concluding observations
The coordination chemistry of technetium is characterized by a range of accessible oxidation states, −I to +VII, several of which are associated robust core geometries, exploitable as platforms for the development of radiopharmaceuticals. The most extensively studied to date are the {Tc(V)O}3+ core and the Tc-organohydrazino cores. The bifunctional chelate approach to radiopharmaceutical design is represented by MAG3 and related complexes of the {Tc(V)O)3+ core and HYNIC-based conjugates for
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