alexa Synthesis, Sigma Receptor Binding Studies, and in vivo Evaluation of Radioiodinated (Z)- and (E)-iodoallyl Analogs of SA4503 | OMICS International | Abstract
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Medicinal Chemistry
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Research Article

Synthesis, Sigma Receptor Binding Studies, and in vivo Evaluation of Radioiodinated (Z)- and (E)-iodoallyl Analogs of SA4503

Rong Xu1, Lisa D. Watkinson2,5, Terry L. Carmack2,5, John R. Lever2,3,5 and Susan Z. Lever1,4*

1Department of Chemistry, University of Missouri, Columbia, MO 65211 USA

2Department of Radiology, University of Missouri, Columbia, MO 65212 USA

3Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212 USA

4University of Missouri Research Reactor Center, University of Missouri, Columbia, MO 65211 USA

5Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201 USA

*Corresponding Author:
Susan Z. Lever
PhD, Room 125 Chemistry Building, University of Missouri
601 South College Avenue, Columbia, MO 65211 USA
Tel: (573) 882-8395
Fax: (573) 882-2754
E-mail: [email protected]

Received date: July 30, 2012; Accepted date: October 10, 2012; Published date: October 12, 2012

Citation: Xu R, Watkinson LD, Carmack TL, Lever JR, Lever SZ (2012) Synthesis, Sigma Receptor Binding Studies, and In Vivo Evaluation of Radioiodinated (Z)- and (E)-iodoallyl Analogs of SA4503. Med chem 2:131-136. doi:10.4172/2161-0444.1000128

Copyright: © 2012 Xu R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


SA4503, a potent σ1 receptor agonist, is under study for functional recovery after stroke, and has been tested for treatment of major depression. Recent behavioral studies indicate that SA4503 can also display antagonist properties, and attenuates psychostimulant-induced hyperactivity in animal models. Further, SA4503 labeled with carbon-11 (halflife 20.4 min), or analogs labeled with fluorine-18 (half-life 109.7 min), are useful for PET studies of the σ1 receptor. Analogs labeled with iodine-123 (13.2 h half-life) would have potential as SPECT imaging agents, while analogs labeled with iodine-125 (60.1 d half-life) could be used routinely in laboratory studies. Toward these ends, we describe the synthesis and radiolabeling, as well as in vitro and in vivo binding studies, of two SA4503 analogs where the 4-methoxy group of the dimethoxyphenethyl moiety is replaced by either a (Z)- or (E)-iodoallyloxy substituent. The iodoallyl groups were introduced by base-promoted coupling of stannylated alkylating agents to 4-O-des-methyl-SA4503, followed by iododestannylation with retention of configuration. Both (Z)- and (E)-iodoallyl-SA4503 displayed moderately high affinities for σ1 and σ2 receptors in vitro (Ki values 11-18 nM). The corresponding radioiodinated ligands were prepared in good yields (57-58%), with high purities (>97%) and high specific activities (>2000 mCi/μmol). Both radioligands readily crossed the blood-brain-barrier of mice, although their log D7.4 values of 3.6 were relatively high. Haloperidol pretreatment defined a modest degree of specific binding to σ1 receptors, but only for the [125I]-labeled (E)-isomer in mouse brain (28%) and liver (25%) at 60 min. Thus, these particular radioligands are not well suited to in vivo studies. More significantly, the work shows that σ receptors display substantial tolerance to bulky structural modifications of SA4503, a feature that might aid in the future development of possible therapeutics based on the SA4503 scaffold.


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