Development of a novel radiobromine-labeled sigma-1 receptor imaging probe

Abstract

Introduction: Sigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4-bromophenyl)piperidino]cyclohexanol [(+)-pBrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)-pBrV. This radiobrominated (+)-pBrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)-pBrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2-hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using ⁷⁶Br, in these initial studies, we used ⁷⁷Br because of its longer half-life.

Methods: (+)-[⁷⁷Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[⁷⁷Br]BrV-OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice.

Results: The lipophilicity and affinity for sigma-1 receptor of (+)-[⁷⁷Br]BrV-OH were lower than those of (+)-[⁷⁷Br]pBrV. (+)-[⁷⁷Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU-145 tumor-bearing mice,. Although (+)-[⁷⁷Br]pBrV was retained in most tissues, (+)-[⁷⁷Br]BrV-OH was cleared from these tissues. In blocking studies, the co-injection of SA4503 significantly decreased the tumor uptake of (+)-[⁷⁷Br]BrV-OH.

Conclusion: These results indicate that (+)-[⁷⁶Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging.

Keywords: Radiobromine; Sigma receptor; Tumor.