Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling

Abstract

A range of macrocyclic and acyclic chelators have been reacted with the PET isotope, gallium-68, and their radiolabelling efficiencies have been compared. Structural data for complexes of HBED with Ga3+ are reported.

PIDAZTA: Structurally Constrained Chelators for the Efficient Formation of Stable Gallium‐68 Complexes at Physiological pH

“…However, the cyclic polyaza‐polycarboxylate chelators DOTA and NOTA, which are most frequently used in 68 Ga tracers, do not allow for labeling at neutral pH, single‐digit μ m concentration, and room temperature within a few minutes. However, this was found to be feasible for several acyclic structures at slightly acidic pH as well as for phosphinate‐pendant triazacyclononanes at pH 3 . Against this background, it is remarkable that the optimal pH for labeling of PIDAZTA isomers L1 / L2 lies between 7 and 8, whereas at pH 7.5, nearly quantitative labeling (89.2 and 93.5 % for L1 and L2 , respectively) at room temperature is achieved already at chelator concentrations below 10 μ m (Figure ).…”

“…Those are, for example, large proteins such as antibodies, which is, however,o fl esser relevance for the short-lived 68 Ga. More importantly,s uch properties would provide access to 68 Ga tracers through "shake-and-shoot" kits that is, by simple addition of 68 Ge/ 68 Ga generator eluate to preconditioned vials containing lyophilized precursor and excipients, as known from 99m Tc radiopharmaceuticals. [37] However,t he cyclic polyaza-polycarboxylate chelators DOTA and NOTA, whicha re most frequently used in 68 Ga tracers, do not allow forl abeling at neutral pH, single-digit mm concentration, and room temperature within af ew minutes.H owever, this was found to be feasible for severala cyclics tructures at slightly acidic pH [38] as well as for phosphinate-pendant triazacyclononanes at pH 3. [39,40] Against this background, it is remarkable that the optimal pH for labeling of PIDAZTAi somers L1/L2 lies between 7and 8, whereas at pH 7.5, nearly quantitative labeling (89.2 and 93.5 %f or L1 and L2,r espectively)a t room temperature is achieveda lready at chelator concentrations below 10 mm ( Figure 6).…”

“…Such behavior might be considered counterintuitive because it is fundamentally different from that of many established 68 Ga III chelators, particularlyt hose based on polyazacycloalkanes, which exhibit the corresponding pH optimum at values around3 - [39][40][41] and show as trong influenceo ft emperature on the required chelator concentration (as ag eneral rule, an approximately 30-times lower concentration is required to achieve the same radiolabeling yield at 95 8Ca sc ompared to 25 8C). [38] An explanation might be that formation of L1/L2 complexesf rom Ga n (OH) 3n (the prevalent form of 68 Ga III at neutral pH) [42] and the competing dehydration of this hydroxide, [43] yieldingn onreactive, insoluble [Ga(O)OH] n [44] ("colloidal 68 Ga"), are apparently accelerated to ac omparable extentu pon heating (Scheme 3; dk 1 /dT % dk 2 /dT), essentially resulting in similarl abeling yields over aw ide range of temperatures.…”

Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and Applications

“…The THP derivative (THP‐mal) was coupled the C‐terminus of a cysteine residue of the scFv via a maleimide linker and labelled 68 Ga at room temperature and neutral pH achieving RCY >95 % without further purification. The THP ligand system is proving to be a highly effective chelator for 68 Ga that shows excellent stability …”

Radiolabeling and in vitro evaluation of a new 5‐fluorouracil derivative with cell culture studies

“…While pertechnetate is the most stable state in aqueous solution, technetium compounds have been prepared with oxidation states from 1− to 7+. To promote binding of 99m Tc with the synthesized molecule, reducing agents were used to reduce 99m Tc from the +7 oxidation state to more reactive +5 oxidation state . In this study, [ 99m Tc]Tc E was prepared by using stannous chloride.…”