Radiosynthesis and in vivo evaluation of a novel σ₁ selective PET ligand

The σ₁ receptor is an important target for CNS disorders. We previously identified a σ₁ ligand TZ3108 having highly potent (K_i-σ1 = 0.48 nM) and selective affinity for σ₁ versus σ₂ receptors. TZ3108 was ¹⁸F-labeled with F-18 for in vivo evaluation. Biodistribution and blocking studies of [¹⁸F]TZ3108 in male Sprague-Dawley rats demonstrated high brain uptake, which was σ₁-specific with no in vivo defluorination. MicroPET studies in cynomolgus macaques showed high brain penetration of [¹⁸F]TZ3108; the regional brain distribution was consistent with that of the σ₁ receptor. Pseudo-equilibrium in the brain was reached ~ 45 min post-injection. Metabolite analysis of [¹⁸F]TZ3108 in NHP blood and rodent blood and brain revealed that ~ 70% parent remained in the plasma of NHPs 60 min post-injection and the major radiometabolite did not cross the blood-brain barrier in rats. In summary, the potent, selective and metabolically stable σ₁ specific radioligand [¹⁸F]TZ3108 represents a potentially useful PET radioligand for quantifying the σ₁ receptor in the brain.