Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent.

Background: Sigma 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.

Results: The 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.

Conclusions: The results indicate that radioiodinated (+)-IV-OH holds a potential as a sigma receptor imaging agent.