Synthesis, radioiodination and in vitro and in vivo sigma receptor studies of N-1-allyl-ND́-4-phenethylpiperazine analogs

Susan Z. Lever, Rong Xu, Kuo Hsien Fan, Emily A. Fergason-Cantrell, Terry L. Carmack, Lisa D. Watkinson, John R. Lever

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Introduction: Sigma-1 (σ1) receptor radioligands are useful for basic pharmacology studies and for imaging studies in neurology, psychiatry and oncology. We derived a hybrid structure, N-1-allyl-ND́-4-phenethylpiperazine, from known ligands TPCNE and SA4503 for use as a scaffold for development of radioiodinated σ1 receptor ligands. Methods: E-and Z-N-1-(3'-iodoallyl)-ND́-4-(3",4"-dimethoxyphenethyl)-piperazine (E-1 and Z-1), N-1-allyl-ND́-4-(3',4'-dimethoxyphenethyl)-piperazine (2) and E-N-1-(3'-iodoallyl)-ND́-4-(3"-methoxy-4'D́-hydroxyphenethyl)-piperazine (3) were synthesized. Affinities for σ1 and σ2 receptors were determined. [125I]E-1 and [125I]Z-1 were prepared and evaluated in vivo in mice. [125I]E-1 was further evaluated in σ1 receptor binding assays in vitro. Results: E-1 displayed moderately high apparent affinity (15 nM) for σ1 sites and 84-fold selectivity against σ2 sites. Z-1 showed similar σ1 affinity, but only 23-fold selectivity. In contrast, 2 exhibited poor binding to both subtypes, while 3 had good affinities but poor selectivity. E-1 profiled as a probable antagonist in the phenytoin shift assay. [125I]E-1 and [125I]Z-1 were prepared in good yields and with high specific radioactivities. Log D7.4 values (2.25 and 2.27) fall within the optimal range for in vivo studies. Both radioligands selectively labeled σ1 receptors in mouse brain and peripheral organs in vivo. [125I]E-1 showed a higher level of specific binding than [125I]Z-1 and displayed good metabolic stability. Further, [125I]E-1 selectively labeled σ1 receptors in mouse brain homogenates (Kd 3.79 nM; Bmax=599 fmol/mg protein). Conclusions: [125I]E-1 is a selective σ1 receptor radioligand that exhibits properties amenable to in vitro and in vivo studies, with possible extension to single photon emission computed tomography using iodine-123.

Original languageEnglish (US)
Pages (from-to)401-414
Number of pages14
JournalNuclear Medicine and Biology
Issue number3
StatePublished - Apr 2012
Externally publishedYes


  • Allylpiperazines
  • I-125
  • Sigma receptors

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research


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