A Triazacyclononane‐Based Bifunctional Phosphinate Ligand for the Preparation of Multimeric ⁶⁸Ga Tracers for Positron Emission Tomography

Abstract

For application in positron emission tomography (PET), PrP9, a N,N',N''-trisubstituted triazacyclononane with methyl(2-carboxyethyl)phosphinic acid pendant arms, was developed as (68)Ga(3+) complexing agent. The synthesis is short and inexpensive. Ga(III) and Fe(III) complexes of PrP9 were characterized by single-crystal X-ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The Ga(III) complex possesses a high thermodynamic stability (log K([GaL])=26.24) and a high degree of kinetic inertness. (68)Ga labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO(2)-based (68)Ge/(68)Ga generator (typically consisting of 0.1 M HCl) can be directly used for labeling purposes. The rate of (68)Ga activity incorporation at pH 3.3 and 20 degrees C is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.

Development of 68Ga-labeled multivalent nitroimidazole derivatives for hypoxia imaging

“…Moreover, protection is not required before conjugation with ligands by amide formation [48,58]. The nitroimidazole residue, 2-(2-nitroimidazolyl)ethylamine hydrochloride was also synthesized according to a previously published method [53,54].…”

“…Actually, NOTA-based ligands showed higher selectivity towards Ga 3+ ion and their complexes are more stable, as the size of the NOTA cavity is almost ideal for this ion [40,48]. However, application of NOTA for a targeted PET probe design is restricted because of its limited bifunctionality.…”

“…If a molecule has two or more nitroimidazole moieties, then it would be trapped in the hypoxic cells with higher probability. Recent attention in ligand design has been focused on studying and optimising chelators N-functionalised with three pendant arms containing sites for both coordination and conjugation, and developed 1,4,7-triazacyclononane-1,4,7-triglutaric acid (NOTGA, 2, Figure 5) or 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP, 3, Figure 5) for multivalent conjugation of ligands to the three pendant arms and 68 Ga labeling ( Figure 5) [47,48,58] . Compared to the other ligands, synthesis of TRAP is more simple, fast and scalable.…”

“…Compared to the other ligands, synthesis of TRAP is more simple, fast and scalable. Moreover, protection is not required before conjugation with ligands by amide formation [48,58]. Another advantage of the phosphinate based chelators is phosphonate donating groups are much less susceptible to transmetalation when compared with acetic acid donors.…”

“…The above studies has been used to form trimeric bioconjugate species although keeping the coordinating atoms for 68 Ga radiolabeling. Further studies showed that 68 Ga-labeled trivalent derivatives of TRAP and NODGA derivatives have higher binding affinity and tumor accumulation than their monovalent and bivalent counterparts [47,48,[58][59][60].…”