Abstract
BackgroundSigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. As a result, (+)-[125I]pIV showed high tumor uptake in biodistribution experiments. However, the accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH).Methods(+)-[125I]IV-OH was prepared by the chloramine T method from the precursor. The partition coefficient of (+)-[125I]IV-OH was measured. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[125I]IV-OH and (+)-[131I]pIV into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[125I]IV-OH mixed with an excess amount of ligand into DU-145 tumor-bearing mice.ResultsThe hydrophilicity of (+)-[125I]IV-OH was much higher than that of (+)-[125I]pIV. In biodistribution experiments, (+)-[125I]IV-OH and (+)-[131I]pIV showed high uptake in tumor tissues at 10-min post-injection. Although (+)-[131I]pIV tended to be retained in most tissues, (+)-[125I]IV-OH was cleared from most tissues. In the liver, the radioactivity level of (+)-[125I]IV-OH was significantly lower at all time points compared to those of (+)-[131I]pIV. In the blocking studies, co-injection of an excess amount of sigma ligands resulted in significant decreases of tumor/blood uptake ratios after injection of (+)-[125I]IV-OH.ConclusionsThe results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.
Highlights
Sigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents
Preparation of (+)-[125I]IV-OH (+)-[125I]IV-OH was prepared by the chloramine-T method [27]
Biodistribution experiments of (+)-[125I]IV-OH and (+)-[131I]pIV in tumor-bearing mice Table 2 lists the biodistribution of (+)-[125I]IV-OH and (+)-[131I]pIV in DU-145 tumor-bearing mice. (+)-[125I]IV-OH showed high uptake in tumor and low radioactivity levels in blood and muscle as well as (+)-[131I]pIV. (+)-[131I]pIV tended to be retained in most tissues, especially tumor
Summary
Sigma receptors are highly expressed in human tumors and should be appropriate targets for developing tumor imaging agents. We synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol ((+)-pIV), with a high affinity for sigma receptors and prepared radioiodinated (+)-pIV. The accumulation of radioactivity in normal tissues, such as the liver, was high. We supposed that some parts of the accumulation of (+)-pIV in the liver should be because of its high lipophilicity, and prepared and evaluated a more hydrophilic radiolabeled vesamicol analog, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-iodophenol ((+)-IV-OH). Sigma receptors were proposed as a new subtype of opioid receptors in 1976 [1]. The sigma-1 receptor subtype has been cloned from various tissues and species [3]. The sigma-2 receptor subtype, whose gene remains to be cloned, has been identified as being progesterone receptor membrane component 1 [5]. Sigma receptor ligands could be candidate drugs as neuroprotective agents after a stroke or head trauma [7], as antidepressant agents [8], as anti-amnesic agents [9], as analgesic agents [10], for alcohol abuse [11], and so on
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