⁶⁸Ga-DATATOC: Synthesis, radiolabeling and first in vivo studies

Objectives: ⁶⁸ Ga-DOTATOC is currently used as standard for diagnostic imaging of neuroendocrine tumors (NETs) and its metastases. Radiolabeling can be performed manually and automated at 95 °C. In order to approach application of ⁶⁸ Ga following a kit-type procedure, a DATA-based chelator (6-Amino-1,4-diazepine-triacetate) was used as it has shown to radiolabel under very mild conditions. Conjugation with TOC may enable radiolabeling of the peptide at room temperature.
Methods: DATATOC was synthesized in a seven step synthesis. Radiolabeling with ⁶⁸ Ga was performed manually at room temperature and stability was assessed in human serum. An automated setup was also examined, using the Modular-Lab eazy (Eckert & Ziegler, Berlin, Germany). First in vivo studies using MPC-mCherry tumor bearing mice were performed and compared with ⁶⁸ Ga-DOTATATE.
Results: Radiolabeling was performed at room temperature using N2 solution, NaOAc-buffer and 14 nmol DATATOC. Within 3 min a RCY of 96.3 ± 1.2 % was obtained. Stability was tested in human serum over a period
of 2 h (Δ = 1.3 %). Automated labeling with 23 nmol precursor achieved quantitative complexation of ⁶⁸ Ga (> 99 %). In vivo PET/CT-studies with 68Ga-DATATOC indicate a high specific uptake in the tumor region after 10 min (SUV of 3.73 ± 1.49). In a blocking study with OC, the SUV in the tumor was reduced to 0.45 ± 0.15. In addition, ⁶⁸ Ga-DATATOC showed high stability in mouse plasma with 93.7 % of the tracer remaining intact after 120 min. Compared to ⁶⁸ Ga-DOTATATE a faster renal excretion of the tracer was observed.
Conclusions: DATATOC can be labeled with ⁶⁸ Ga in a manual or automated setup rapidly at room temperature, offering significant advantages over similar DOTA-based derivatives. Because of quantitative labeling yields, product purification is unnecessary. Furthermore, first in vivo studies confirm excellent targeting and excretion characteristics for the novel tracer. With the perspective towards a kit-type formulation, the superior characteristics
of this new compound pave the way for a new generation of ⁶⁸ Ga radiopharmaceuticals.