Abstract
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Objectives Sigma receptors are highly expressed in a variety of human tumors. Therefore, sigma receptors are appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with high affinity for sigma receptors, and prepared radioiodinated (+)-pIV. As a result of the biodistribution experiments in tumor-bearing mice, (+)-[125I]-pIV showed high uptake in the tumors. However, the accumulation of radioactivity in non-target tissues, such as liver, was high. We hypothesized that the high accumulations and long retention of radioactivity in non-target tissues should be derived from high lipophilicity of (+)-pIV, and prepared a more hydrophilic radiolebeled vesamicol analog ((+)-IV-OH).
Methods (+)-[125I]-IV-OH was prepared by the chloramine T method from the precursor, which was synthesized with overall yield of 7.2% from phenylpiperidine. The partition coefficient of (+)-[125I] IV-OH was measured. Biodistribution experiments were performed by intravenous administration of mixed solution of (+)-[125I]-IV-OH and (+)-[131I]-pIV into DU-145 tumor bearing mice.
Results The hydorophilicity of (+)-[125I]-IV-OH was much higher than that of (+)-[125I]-pIV (log P value: 1.13 ± 0.02 and 2.08 ± 0.02). In biodistribution experiments, (+)-[125I]-IV-OH and (+)-[131I]-pIV showed high uptakes in tumor after 10 min postinjection (9.6 ± 0.6 and 7.2 ± 0.4 %ID/g). Although (+)-[131I]-pIV showed long retention in liver, (+)-[125I]-IV-OH disappeared from liver (10.3 ± 0.6 and 0.06 ± 0.03 %ID/g at 24 h). In blocking study, co-injection of an excess amount of sigma ligands resulted in a significant decrease of tumor uptake after injection of (+)-[125I]-IV-OH (without sigma ligand: 5.4 ± 1.6, SA4503: 1.6 ± 0.3, (+)-pIV: 2.0 ± 0.3, haloperidol: 3.0 ± 1.1 %ID/g at 1 h, respectively).
Conclusions These results indicate that radioiodinated (+)-IV-OH holds great potential as a sigma receptor imaging agent