Alkanolammonium Protic Ionic Liquids for Low Temperature ⁶⁸Ga‐Radiolabeling of DOTA‐Functionalized Compounds

Abstract

Nowadays, the radiolabeling of small biomolecules with isotope 68Ga is one of the important directions in the field of Positron‐Emission Tomography (PET). The right choice of buffer for reaction helps to achieve optimal conditions for higher yields. Earlier, we found that protic ionic liquids based on tris(2‐hydroxyethyl)ammonium and tris(hydroxymethyl)methyl ammonium salts are suitable buffers for the chelation of the 68Ga to the PSMA‐HBED‐CC (a peptide with an acyclic chelator). Herein we describe the labeling of p‐SCN‐Bn‐DOTA (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) chelator and peptides (DOTA‐NOC, DOTA‐TATE, and PSMA‐617) with gallium‐68 isotope in media of alkanolammonium buffers based on tris(2‐hydroxyethyl)ammonium (TEA), tris(hydroxymethyl)methyl ammonium (TRIS) and N‐phenyl‐bis(2‐hydroxyethyl)ammonium (PDA) salts. Besides, for the first time, we present results of low‐temperature 68Ga‐complexation in the presence of organic solvents additives. An essential consequence of this study is that for the series of alkanolammonium buffers, high radiochemical conversions were achieved upon incubation of reaction media under 37 °C.

Protic Ionic Liquids Based on BIS‐TRIS Carboxylates: Synthesis, Structural Characterization and Buffer Activity

“…The 68 Ga‐DOTA complex, as a rule, is easily formed at 95 °C and the addition of ethanol as a co‐solvent with high radiochemical conversion (RCC) [22] . Earlier, our group showed that 68 Ga complexes with BCAs and clinically significant peptides could be obtained in the medium of hydroxyalkylammonium salts at 37 °C and using acetone as a co‐solvent [9b] …”

N-Benzylethanolammonium Ionic Liquids and Molten Salts in the Synthesis of 68Ga- and Al18F-Labeled Radiopharmaceuticals

“…Furthermore, it is common knowledge that DOTA makes stable complexes with many isotopes in addition to gallium-68 and provides stability of bioconjugates in vitro and in vivo. The full evaluation was carried out with using of high-temperature (HT) and low-temperature (LT) radiolabeling protocols [ 23 , 25 , 26 , 36 ].…”

“…Surprisingly, a similar result was found for salts 5 and 6 . In our previous works [ 23 , 24 , 25 , 26 , 36 ], ILs containing 2-methylphenoxyacetate and 4-chloro-2-methylphenoxyacetate anions as buffering agents provide almost quantitative RCCs for the reaction of 68 Ga radioisotope with the DOTA chelator. BEA salts 4 , 9 and 10 showed average RCCs in the 40–65% range.…”

“…Alkanolammonium ILs are a promising alternative to zwitterionic buffer HEPES in 68 Ga-radiolabeling reactions. We have previously shown that alkanolammonium ILs are significantly more efficient under the low-temperature 68 Ga-radiolabeling protocol (37 °C) compared to the HEPES buffer [ 36 ]. This is a significant advantage, since some biomolecules (such as proteins) are not resistant to heating up to 90 °C.…”

Contribution of the Scientific School of Academician M.G. Voronkov to the Development of the Chemistry of Biologically Active Atranes (Protatranes and Hydrometallatranes) (A Review)

“…Joint research with Granov Russian Scientific Center of Radiology and Surgical Technologies [ 95 , 96 ] have shown that the synthesized hydroxyalkylammonium carboxylates are promising buffering agents for the preparation of gallium-68 complexes with chelators and peptides. The 68 Ga complexes with a series of clinically important peptides are radiopharmaceuticals important in the nuclear medicine for the diagnostics of various neoplasms.…”