Automated GMP production and preclinical evaluation of Ga-68-TAoS-DAZA

Ziel/Aim Ga-68-TAoS-DAZA is a PET tracer suitable for segmental liver function quantification and gall tree imaging. Liver imaging with PET provides an alternative where established techniques are not applicable due to contraindications (MRI) or limited temporal resolution (SPECT). To enable future clinical studies a GMP compliant synthesis of Ga-68-TAoS-DAZA was required. During synthesis development we encountered problems regarding radiochemical yield and purity, that were investigated. Additionally, a biodistribution study in an in-ovo model was performed.

Methodik/Methods Ga-68-TAoS-DAZA was prepared on an automated synthesizer. HPLC and MS analysis were used to identify the cause of initially low radiochemical yields. As a result of these findings the synthesis procedure was adapted, including radiolabeling at room temperature in HEPES buffer and establishing a two-step SPE purification prior to dilution. Quality control procedures were in accordance with Ph. Eur. requirements. The logP of Ga-68-TAoS-DAZA was determined via shake flask method. Biodistribution studies were performed on ostrich embryos.

Ergebnisse/Results The precursor TAoS-DAZA rapidly decomposes via N-dealkylation in HEPES buffer at 100°C, therefore requiring radiolabeling at room temperature. However, even at 25°C a slight decomposition occurs, resulting in a radiolabeled impurity. By introducing a two-step SPE purification procedure the content of the impurity in the final solution could be lowered to≤2.0%. Quality control of Ga-68-TAoS-DAZA according to the required specifications of the Ph. Eur. gave compliant results. Biodistribution studies confirmed specific liver uptake, which is in accordance with the high logP, and an increase of activity in the intestines over time, indicating biliary excretion.

Schlussfolgerungen/Conclusions Ga-68-TAoS-DAZA can be prepared according to GMP guidelines, which means that a transition into the early clinical phase is now possible. Future studies will give detailed insight into the hepatic transporter interaction.