Dopamine D1 Receptor Agonist PET Tracer Development: Assessment in Non-Human Primates.

Objective: Non-catechol based high affinity selective dopamine D1 receptor (D1R) agonists were recently described, and candidate PET ligands were selected based on favorable properties. The objective of this study was to characterize in vivo in non-human primates two novel D1R agonist PET radiotracers, racemic 18F-MNI-800 and its more active atropisomeric (-)-enantiomer 18F-MNI-968. Methods: Ten brain PET experiments were conducted with 18F-MNI-800 in two adult rhesus macaques and two adult cynomolgus macaques, and eight brain PET experiments were conducted with 18F-MNI-968 in two adult rhesus macaques and two adult cynomolgus macaques. PET data were analyzed with both plasma-input and reference-region based methods. Whole-body PET images were acquired with 18F-MNI-800 for radiation dosimetry estimates in two adult rhesus macaques. Results:18F-MNI-800 and 18F-MNI-968 exhibited regional uptake consistent with D1 receptor distribution. Specificity and selectivity were demonstrated by dose-dependent blocking with the D1 antagonist SCH-23390. 18F-MNI-968 showed a 30% higher specific signal compared to 18F-MNI-800, with a binding potential BPND of ~0.3 in the cortex and ~1.1 in the striatum. Dosimetry radiation exposure was favorable, with an effective dose of ~0.023 mSv/MBq. Conclusion:18F-MNI-968 (18F-PF-0110) has significant potential as a D1R agonist PET radiotracer, and further characterization in human subjects is warranted.