Objectives: Metal complexes of macrocyclic ligands play important role in medical applications. Formation of these complexes is often quite slow, which is inconvenient for short lived radioisotopes used in therapy or PET and SPECT examinations. In order to accelerate the formation reactions and to avoid the denaturation of the biologically active fragment in conjugates, Rösch et al. proposed an organic solvent – water mixture for the synthesis of M(DOTA) complexes with trivalent metal ions at ambient temperature.¹ Our aim is to explore the kinetics and suggest mechanisms to explain the experimental findings.

Results: Formation kinetics and mechanisms of lanthanide(III)-DOTA complexes in aqueous solutions is known from our previous work.² The reaction goes through a long lived intermediate, *Ln(H₂DOTA), in which the Ln³⁺ ion is kept far from the macrocyclic-ring by the four acatetate groups, while two diagonal ring nitrogens are protonated. The rate determining step is the deprotonation and the concerted structural rearrangement of the intermediate resulting in the tightly wrapped Ln(III) in the cavity of the DOTA, i.e. the final product of the reaction. Similar mechanism can be proposed for water-ethanol solvent mixtures, the increase in the reaction rate can be attributed to the decreased protonation constants of ring nitrogen donors both in the free ligand and in the *Ln(H₂DOTA) intermediate. The mechanisms is similar for the formation of gallium(III)-DOTA complex, although further fine differences have been detected and correlated to the role of the gallium(III)-hydroxo complexes.

Conclusion: Detailed kinetic data for water-ethanol mixture are useful to optimize the labeling procedure of DOTA-conjugates with different Ln³⁺ and Ga³⁺-isotopes of medical importance at ambient temperature. 

¹ F. Rösch et al., EJNMMI Radiopharm. Chem., 2016, 1, 6.

² a) É. Tóth et al., Inorg.  Chem., 1994, 33, 4070. b) L. Burai et al., Dalton Trans., 1998, 243.