[¹¹C]R129144 as a putative PET ligand for the adrenergic α2 receptor

Objectives A PET ligand for the adrenergic α2 receptor (α2AR) would be of interest for accelerating drug development aimed at this receptor. R129144 has high affinity and selectivity for the α2AR. In addition, it has an advantageous pharmaco-kinetic profile and is amenable to labelling with ¹¹C. The radiosynthesis of ³H- and ¹¹C labelled R129144, the in vitro brain autoradiography of [³H]R129144 and biodistribution in rats of [¹¹C]R129144 are reported.

Methods [¹¹C]R129144 was radiolabeled with [¹¹C]methyl triflate from the precursor R125460 and reaction conditions were optimized. In addition, for in vitro autoradiography experiments, [³H]R129144 was synthesized based on the same precursor and [³H]CH₃I. Autoradiography was performed using 20 µm coronal slices from rat brain. The biodistribution of [¹¹C]R129144 in male wistar rats was determined at 5, 10, 20 and 30 minutes post injection (pi). Specificity of brain uptake was assessed from an identical biodistribution study, but now after pretreatment with the selective α2 antagonist R107474 (1 mg.kg^-1, 30 min. prior to the tracer injection).

Results [³H]R129144 in vitro autoradiography showed heterogeneous distribution in rat brain slices with high, selective and reversible binding in α2AR rich brain areas, such as entorhinal cortex (EC) septum (Se) and hippocampus (Hp). The cerebellum was defined as non-target tissue, being devoid of α2AR’s. [¹¹C]R129144 was synthesized in 34-45% decay corrected radiochemical yield with >99% (radio)chemical purity and a specific activity of 77-190 GBq.µMole^-1. The biodistribution studies revealed fast clearance from blood, high uptake in the target brain areas EC, Se and Hp (0.8-1.2 %), and high target to non-target tissue ratio’s (up to 4.8 for EC at 30 min pi). Uptake in EC, Se and Hp was blocked by pretreatment with R107474.

Conclusions [¹¹C]R129144 was successfully synthesized and initial studies in rats showed its potential as a PET ligand for the α2AR.

Research Support Johnson & Johnson PRD, Beerse, Belgium