Development and evaluation of a radiobromine-labeled sigma ligand for tumor imaging

Sigma receptors are appropriate targets for tumor imaging because they are highly expressed in a variety of human tumors. Previously, we synthesized a vesamicol analog, (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol ((+)-pIV), with high affinity for sigma receptors, and prepared radioiodinated (+)-pIV. In this study, to develop a radiobromine-labeled vesamicol analog as a sigma receptor imaging agent for PET, nonradioactive and radiobromine-labeled (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol ((+)-pBrV) was prepared and evaluated in vitro and in vivo. In these initial studies, (77)Br was used because of its longer half-life.

(+)-[(77)Br]pBrV was prepared by a bromodestannylation reaction with radiochemical purity of 98.8% after HPLC purification. The partition coefficient of (+)-[(77)Br]pBrV was measured. In vitro binding characteristics of (+)-pBrV to sigma receptors were assayed. Biodistribution experiments were performed by intravenous administration of a mixed solution of (+)-[(77)Br]pBrV and (+)-[(125)I]pIV into DU-145 tumor-bearing mice.

The lipophilicity of (+)-[(77)Br]pBrV was lower than that of (+)-[(125)I]pIV. As a result of in vitro binding assay to sigma receptors, the affinities of (+)-pBrV to sigma receptors were competitive to those of (+)-pIV. In biodistribution experiments, (+)-[(77)Br]pBrV and (+)-[(125)I]pIV showed high uptake in tumor via sigma receptors. The biodistributions of both radiotracers showed similar patterns. However, the accumulation of radioactivity in liver after injection of (+)-[(77)Br]pBrV was significantly lower compared to that of (+)-[(125)I]pIV.

These results indicate that radiobromine-labeled pBrV possesses great potential as a sigma receptor imaging agent for PET.