Medicinal Chemistry

ISSN: 2161-0444

Open Access

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


Rong Xu, Lisa D. Watkinson, Terry L. Carmack, John R. Lever and Susan Z. Lever

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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