![]() ![]() Still, it is reasonable to ask whether this cavity really exists. ![]() 2020 Hancock 1992 Hancock and Martell 1989). However, the idea that a cationic radiometal binds H 4DOTA based on size fit with the interior of a hypothetical cavity associated with the macrocyclic ring has progressively gained widespread acceptance and, as a result, is often applied to the design of metallic radiopharmaceuticals particularly with the new emerging rare-earth radiometals (Stasiuk and Long 2013 Baranyai et al. This hypothetical universal coordination affinity of the DOTA ligand towards radiometals was initially rationalized by considering quantities such as the thermodynamic stability constant, the macrocyclic effect, and the strength of the metal-nitrogen bonds. 2020) able to form stable complexes with a multitude of metallic cations. 2022).Īfter its introduction in radiopharmaceutical chemistry, the macrocyclic ligand 2,2′,2",2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (H 4DOTA) has been popularized as a kind of ‘universal’ polymetallic chelating agent (Stasiuk and Long 2013 Baranyai et al. In this example, the size of the cation is simply interpreted as its volume calculated from the value of its ionic radius, whereas the size of the macrocyclic cavity is conventionally determined by considering the bond distances of the main atoms surrounding the cavity and drawing its boundaries, as measured from X-ray diffraction data (Henrick et al. It has been argued that a stable coordination complex between the alkali metal cation and the crown ether can be formed when there exists an appropriate match between the size of the ion and the cavity size of the crown ether (Liou and Brodbelt 1992). Therefore, to account for the high selectivity of crown ethers for alkali metal ions the model of ‘macrocyclic cavity’ was introduced. Since the outer electron distribution of an alkali metal ion always overlaps that of the noble gas that precedes it in the periodic table, the inherent inertness of this closed-shell electronic configuration prevents the formation of strong covalent bonds between the ligand and the cation. The notion of ‘macrocyclic cavity’ has become popular after Pedersen’s discovery of crown ethers in 1967 and has been used as a key theoretical hypothesis to explain the strong affinity of this class of macrocyclic ligands for alkali metal ions (Pedersen 1967). ConclusionsĪpplication of Euclidean geometry to calculate bond angles in the coordination complex of the ligand H 4DOTA with the Ga +3 ion, supposed to incorporate a hypothetical ‘macrocyclic cavity’, revealed that this conceptual entity has no physical reality and, therefore, cannot be considered a meaningful description of a stable structural arrangement for metallic radiopharmaceuticals. The geometrical analysis was applied to the complex formed by a Ga 3+ ion coordinated to H 4DOTA as model compound. Resultsīased on X-ray structural data of metallic complexes formed by the ligand H 4DOTA upon coordination with a variety of metals, an elementary argument based on Euclidean geometry is presented here that questions the existence of the hypothetical ‘macrocyclic cavity’ within the chelator macrocycle. This approach has become popular in the design of radiopharmaceuticals containing radiometals and H 4DOTA as chelating group. ![]() It Is hypothesized that a close matching between the size of the macrocyclic cavity and that of the metallic ion is a key parameter to ensure the high-yield formation of stable coordination metal-DOTA complex. The hypothetical concept of ‘macrocyclic cavity’ is largely employed as useful model to interpret the affinity of metal ions for the macrocyclic chelating ligand 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (H 4DOTA). ![]()
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