On the development of a novel non-peptidic ¹⁸F-labeled radiotracer for in vivo imaging of oxytocin receptors with positron emission tomography

Objectives:

The peptide oxytocin is synthesized in the hypothalamus and acts as neurotransmitter to regulate a diverse range of CNS functions. Its receptor (OTR) is expressed in specific brain areas related to psychiatric diseases. So far, a non-invasive investigation of the OTR in brain is hampered by a lack of suitable radiotracers. To develope a PET ligand with high affinity toward OTR, we synthesized a series of fluorinated non-peptidic small molecules and performed radiofluorination of a selected candidate to investigate its in vivo properties in mice and pigs.

Methods:

Binding affinities of the compounds to the human OTR were determined by radioligand displacement studies. The radiosynthesis of [¹⁸F]ABX163 (KD = 12.3 nM) was performed via thermal and microwave heating (see scheme 1). Metabolism and organ distribution of the radiotracer were studied in female CD-1 mice. Dynamic PET scans were performed in mice (animal PET/MR; 60 min) and in one female piglet (PET; 120 min).

Results:

Using microwave heating for the synthesis of [¹⁸F]ABX163 provided higher RCY in shorter reaction time compared to thermal heating (RCY 25.4 ± 3.1% (n=5); SA 35-160 GBq/µmol; RP > 97%). Both organ distribution and dynamic PET imaging studies revealed limited uptake of the radiotracer in mouse brain (SUVmean = 0.04). Besides, significant uptake in the pituitary gland was observed (SUV55 min p.i. = 0.85), which indicates target-specific binding of [¹⁸F]ABX163. By a dynamic PET study in pig, a mean SUV of 0.43 was estimated for the whole brain at 120 min p.i. A two fold higher uptake was observed in the olfactory bulb (SUV120 min p.i. = 0.73), a region with high expression of OTR. In vitro autoradiography studies on rat and pig brain slices revealed an interaction of [¹⁸F]ABX163 with several off target receptors.

Conclusion:

Due to the low brain uptake and the insufficient selectivity, [¹⁸F]ABX163 is not suitable for imaging of OTR in living brain.

Acknowledgment: The authors thank the SAB (Sächsische AufbauBank) for funding this project.