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

Hongjun Jin, Jinda Fan, Xiang Zhang, Junfeng Li, Hubert P. Flores, Joel S. Perlmutter, Stanley M. Parsons, Zhude Tu

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The σ1 receptor is an important target for CNS disorders. We previously identified a σ1 ligand TZ3108 having highly potent (Ki-σ1 = 0.48 nM) and selective affinity for σ1versus σ2 receptors. TZ3108 was 18F-labeled 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.

Original languageEnglish
Pages (from-to)1669-1677
Number of pages9
JournalMedChemComm
Volume5
Issue number11
DOIs
StatePublished - Nov 1 2014

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