Abstract
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Objectives Sigma receptors could be targets for tumor imaging. Previously, we prepared a radiobrominated vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol ((+)-pBrV), with high affinity for sigma receptors. The (+)-pBrV showed high tumor uptake in tumor-bearing mice. But, the accumulation of radioactivity in normal tissues, such as liver, was also high. We supposed that some parts of the non-specific tissue accumulation of (+)-pBrV could be derived from its high lipophilicity, and then prepared and evaluated a more hydrophilic compound, (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH]. Although our purpose is developing PET tracer using Br-76, in these initial studies, Br-77 was used because of its longer half-life.
Methods In vitro binding characteristics of (+)-BrV-OH to sigma receptors were assayed. (+)-[Br-77]BrV-OH was prepared by the chloramine T method. The partition coefficient of (+)-[Br-77]BrV-OH was measured. Cell uptake studies of (+)-[Br-77]BrV-OH were performed in monolayer cultures of DU-145 prostate cancer cell lines. Biodistribution experiments were performed by intravenous administration of (+)-[Br-77]BrV-OH into DU-145 tumor-bearing mice. Blocking studies were performed by intravenous injection of (+)-[Br-77]BrV-OH mixed with an excess amount of ligand, SA4503 into DU-145 tumor-bearing mice.
Results (+)-BrV-OH (Ki = 13.7 nM for sigma 1, Ki = 28.7 nM for sigma 2) showed greater affinity for sigma receptors as did (+)-vesamicol (Ki = 18.4 nM for sigma 1, Ki = 122.4 nM for sigma 2), which is a mother compound. (+)-[Br-77]BrV-OH was prepared with radiochemical yield of 28% and radiochemical purity of 95% after purification by RP-HPLC. The lipophilicity of (+)-[Br-77]BrV-OH (log P value = 1.23) was lower than that of (+)-[Br-77]pBrV (log P value = 1.58). Cell uptake studies demonstrated a rapid uptake of (+)-[Br-77]BrV-OH during the initial phase in DU145 cells. The uptake of (+)-[Br-77]BrV-OH was remarkably inhibited in the presence of a sigma ligand, haloperidol at 10 μM. In biodistribution experiments, (+)-[Br-77]BrV-OH showed high uptake in tumor. Although (+)-[Br-77]pBrV tended to be retained in most tissues, (+)-[Br-77]BrV-OH was cleared from most tissues. In the blocking studies, co-injection of an excess amount of SA4503 significantly decreased tumor / blood uptake ratios after injection of (+)-[Br-77]BrV-OH.
Conclusions These results indicate that radiobromine-labeled (+)-BrV-OH possesses great potential as a sigma receptor imaging agent for PET.