Novel cyclopentadienyl tricarbonyl (99m)tc complexes containing 1-piperonylpiperazine moiety: potential imaging probes for sigma-1 receptors.

Abstract

We report the design, synthesis, and evaluation of a series of novel cyclopentadienyl tricarbonyl (99m)Tc complexes as potent σ1 receptor radioligands. Rhenium compounds 3-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)propylcarbonylcyclopentadienyl tricarbonyl rhenium (10a) and 4-(4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl)butylcarbonylcyclopentadienyl tricarbonyl rhenium (10b) possessed high in vitro affinity for σ1 receptors and moderate to high selectivity for σ2 receptors and the vesicular acetylcholine transporter. Biodistribution studies in mice demonstrated high initial brain uptake for corresponding (99m)Tc derivatives [(99m)Tc]23 and [(99m)Tc]24 of 2.94 and 2.13% injected dose (ID)/g, respectively, at 2 min postinjection. Pretreatment of haloperidol significantly reduced the radiotracer accumulation of [(99m)Tc]23 or [(99m)Tc]24 in the brain. Studies of the cellular uptake of [(99m)Tc]23 in C6 and DU145 tumor cells demonstrated a reduction of accumulation by incubation with haloperidol, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine (SA4503), or 1,3-di-o-tolyl-guanidine (DTG). Furthermore, blocking studies in C6 glioma-bearing mice confirmed the specific binding of [(99m)Tc]23 to σ1 receptors in the tumor.

• Authors: Xia Wang, Dan Li, Winnie Deuther-Conrad, Jie Lu, Ying Xie, Bing Jia, Mengchao Cui, Jörg Steinbach, Peter Brust, Boli Liu, Hongmei Jia
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 16 Pg. 7113-25 (Aug 28 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25073047 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Molecular Probes
• Organotechnetium Compounds
• Piperazines
• Receptors, sigma
• sigma-1 receptor
• 1-piperonylpiperazine
• Technetium
• SA 4503
• Haloperidol

Topics

• Animals
• Brain (drug effects, metabolism)
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• Glioma (metabolism)
• Haloperidol (pharmacokinetics)
• Ligands
• Male
• Mice, Inbred ICR
• Molecular Imaging (methods)
• Molecular Probes (chemical synthesis, chemistry)
• Organotechnetium Compounds (chemical synthesis, chemistry)
• Piperazines (chemistry, pharmacokinetics)
• Prostatic Neoplasms (diagnosis, metabolism)
• Receptors, sigma (analysis, metabolism)
• Structure-Activity Relationship
• Technetium (chemistry)
• Tissue Distribution