DATATOC: a novel conjugate for kit-type ⁶⁸Ga labelling of TOC at ambient temperature

The widespread acceptance and application of ⁶⁸Ga-PET depends on our ability to develop radiopharmaceuticals that can be prepared in a convenient and suitable manner. A kit-type labelling protocol provides such characteristics and requires chelators that can be radiolabelled under exceptionally mild conditions. Recently the DATA chelators have been introduced that fulfil these requirements. In continuing their development, the synthesis and radiolabelling of the first DATA bifunctional chelator (BFC) and peptide conjugate are described.

A BFC derived from the DATA ligand (2,2'-(6-((carboxymethyl)amino)-1,4-diazepane-1,4-diyl)diacetic acid) has been synthesised in five steps from simple building blocks, with an overall yield of 8 %. DATA^M5-3^tBu (5-[1,4-Bis-tert-butoxycarbonylmethyl-6-(tert-butoxycarbonylmethyl-methyl-amino)-[1, 4]diazepan-6-yl]-pentanoic acid) has been coupled to [DPhe¹][Tyr³]-octreotide (TOC) and the resulting peptide conjugate (DATATOC) radiolabelled with purified ⁶⁸Ga derived via four different ⁶⁸Ge/⁶⁸Ga generator post-processing (PP) methods. The stability and lipophilicity of the radiotracer have been assessed and a kit-type formulation for radiolabelling evaluated. ⁶⁸Ga-DATATOC has been prepared with a > 95 % radiochemical yield (RCY) within 1 (fractionated and acetone-PP) and 10 min (ethanol- and NaCl-PP) at 23 °C (pH 4.2-4.9, 13 nmol). The radiolabelled peptide is stable in the presence of human serum. Lipophilicity of ⁶⁸Ga-DATATOC was calculated as logP = -3.2 ± 0.3, with a HPLC retention time (t_R = 10.4 min) similar to ⁶⁸Ga-DOTATOC (logP = -2.9 ± 0.4, t_R = 10.3 min). Kit-type labelling from a lyophilised solid using acetone-PP based labelling achieves > 95 % RCY in 10 min at 23 °C.

The favourable labelling properties of the DATA chelators have been retained for DATATOC. High radiochemical purity can be achieved at 23 °C in less than 1 min and from a kit formulation. The speed, reliability, ease, flexibility and simplicity with which ⁶⁸Ga-DATATOC can be prepared makes it a very attractive alternative to current standards.