N,1,4-Tri(4-alkoxy-2-hydroxybenzyl)-DAZA: Efficient one-pot synthesis and labelling with 68Ga for PET liver imaging in ovo

Ziel/Aim:

Liver specific PET tracers exhibiting high hepatocellular uptake and biliary excretion could provide an alternative diagnostic tool, where established liver imaging techniques are not applicable due to contraindications and side effects (MRI) or limited temporal resolution (SPECT). The aim of this study was to develop liver specific ⁶⁸Ga radiopharmaceuticals and to evaluate their potential in preclinical investigations.

Methodik/Methods:

Ligands N,1,4-tri(4-alkoxy-2-hydroxybenzyl)-DAZA (alkoxy = Me, Et) were prepared from 1,4-diazepan-6-amine (DAZA) and 4-alkoxy-2-hydroxybenzaldehyde via a one-pot synthesis. The chelators were labelled with ⁶⁸Ga eluate from a ⁶⁸Ge/⁶⁸Ga generator at pH 3.7 – 4.0 and 100 °C, followed by SPE purification. The radiochemical purity was determined via radio TLC and radio HPLC. In vitro stability studies were performed against human serum. Ostrich egg preparation was performed by removing a small piece of the egg shell and puncturing of a vitelline vein with a thin cannula. Dynamic PET imaging was performed with a PET/CT scanner (Biograph mCT40, Siemens, Erlangen, Germany).

Ergebnisse/Results:

The radiotracers [⁶⁸Ga]Ga-TMeOHB-DAZA and [⁶⁸Ga]Ga-TEtOHB-DAZA were stable in vitro over 4hrs. Following administration in ovo the tracers showed rapid accumulation in the liver with uptake values of up to 27%. Excretion into the bowels was observed, starting at ca. 30 min p.i. Compared to liver specific SPECT tracer [^{99 m}Tc]Tc-EHIDA the in ovo PET imaging expectedly showed better image resolution.

Schlussfolgerungen/Conclusions:

Novel aminophenolates TMeOHB-DAZA and TEtOHB-DAZA form ⁶⁸Ga tracers with high kinetic inertness. Due to specific hepatic uptake the radiotracers are suitable for liver and, possibly, biliary imaging with PET as an alternative to SPECT or MRI. Future studies will investigate radiotracer biodistribution and metabolites using ex vivo methods. The in ovo ostrich model has proven a suitable preclinical imaging model that can be used in routine clinical sites, thus presenting an alternative to animal models.

Literatur/References:

[1] Julia Greiser, Christian Kühnel, Helmar Görls, Wolfgang Weigand, Martin Freesmeyer, Dalton Trans. 2018, 47, 9000 – 9007, 10.1039/c8dt01038b.