Abstract
PurposeAAZTA (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) based chelators were initially developed in the context of magnetic resonance imaging. First radiochemical studies showed the capability of AAZTA to form stable complexes with radiolanthanides and moderately stable complexes with 68Ga. For a systematic comparison of the labelling capabilities with current diagnostic and therapeutic trivalent radiometals, AAZTA5 (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine) was synthesized representing a bifunctional version with a pentanoic acid at the carbon-6 atom. To evaluate the effect of adding a targeting vector (TV) to the bifunctional chelator on the complex formation, AAZTA5-TOC was synthesized, radiolabeled and tested in comparison to the uncoupled AAZTA5.MethodsAAZTA5 was synthesized in a 5-step synthesis. It was coupled to the cyclic peptide TOC (Phe1-Tyr3 octreotide) via amide bound formation. AAZTA and AAZTA5-TOC complex formations with 68Ga, 44Sc and 177Lu were investigated at different pH, temperature and precursor amounts. Stability studies against human serum, PBS buffer, EDTA and DTPA were performed.ResultsAAZTA5 and AAZTA5-TOC achieved quantitative labelling (> 95%) at room temperature in less than 5 min with all three nuclides at pH ranges from 4 to 5.5 with low precursor amounts of 1 to 10 nmol. [44Sc]Sc-AAZTA5 complexes as well as [44Sc]Sc-AAZTA5-TOC were completely stable. The 177Lu complexes of AAZTA5 and AAZTA5-TOC showed high stability comparable to the 44Sc complexes. In contrast, the [68Ga]Ga-AAZTA5 complex stability was rather low, but interestingly, [68Ga]Ga-AAZTA5-TOC was completely stable.ConclusionAAZTA5 appears to be a promising bifunctional chelator for 68Ga, 44Sc and 177Lu with outstanding labelling capabilities at room temperature. Complex stabilities are high in the case of 44Sc and 177Lu. While [68Ga]Ga-AAZTA complexes alone lacking stability, [68Ga]Ga-AAZTA5-TOC demonstrated high stability. The latter indicates an interesting feature of [68Ga]Ga-AAZTA5–labelled radiopharmaceuticals.
Highlights
The ongoing development in molecular imaging is focusing more and more on theranostic approaches as they link imaging directly with therapy as well as monitoring of the treatment (Baum and Kulkarni 2012; Baum and Rösch 2013; Rösch et al 2017)
To deprotect the bifunctional acid group, the methyl ester is cleaved with LiOH in dioxane/water to afford 4, while for the evaluation of the free chelator 5 the protective tert-butyl groups were cleaved with Trifluoroacetic acid (TFA) leaving the methyl ester intact
Ready for coupling AAZTA5 could be isolated with a yield of 35% calculated over all reaction steps from the N,N′-dibenzylethylenediamine used in the first reaction step
Summary
The ongoing development in molecular imaging is focusing more and more on theranostic approaches as they link imaging directly with therapy as well as monitoring of the treatment (Baum and Kulkarni 2012; Baum and Rösch 2013; Rösch et al 2017). In this context, patient-individual dosimetry is important for application of long-lived therapeutic nuclides. For theranostic strategies with 177Lu only DOTA can be used, since NOTA derivatives are not suitable for complexing 177Lu. Again, 177Lu-labellig of DOTA-peptides is achieved at temperatures close to 100 °C and optimal labelling pH is around 4
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