Synthesis and Characterization of Rhenium(V) Complexes Having 3-(4-m-Chlorophenylpiperazin-1-yl)butane-1-thiol as Coligand toward 5HT2ASpecific Radiopharmaceuticals

Abstract

The development of technetium-99m-labeled imaging agent for brain receptors is still a formidable challenge in radiopharmaceutical research. The specific serotonin receptor-binding imaging agent, particularly the 5-HT2 receptor antagonist, attracts great attention because it is known to be involved in many neurological and psychological diseases including Alzhemier’s disease and depression. Many imaging agents suitable for positron emission tomography bearing C and F as a radiotracer were developed on the basis of known 5HT2A receptor antagonist. Imaging agents for single photon emission computed tomography (SPECT) labeled with I or 125 I were also developed. Preparation of technetium-99m-labeled imaging agent for the 5HT2A receptor stems from mimicking the receptor binding compounds as biologically active molecules (BAMs) which bind to the metals to form proper metal complex with other ligands to accommodate all coordination sites. A novel “3+1” mixed ligand rhenium oxo complex can be generated from the combination of tridentate ligand and monodentate BAM. A few reports describe the synthesis and evaluation of technetium(V) and rhenium(V) complex for 5HT2A serotonin receptor binding based on the ketanserin (1) and its derivatives. A ligand used for BAM based on ketanserin can be designed on the basis of two structural units i.e. quinazoline as part A and phenyl piperidinyl ketone as part B. Either part A or B can be used for BAM while the other part goes as metal binding site. Among two approaches, part B, phenyl piperidinyl ketone site is more favorable for biologically active ligand because it is longer and adjustable. The size and structural similarity to replace part A quinazoline ring is more acceptable and its metal complex with technetium99m showed better imaging agent. Recently ketanserin surrogate 2 showed very selective and potent binding activity toward 5HT2A that may serve as a template to design a new technetium-99m-labelled imaging agent. Triazolopyridin-3one can be replaced by the relatively small metal complex while the pendent 1-alkyl-4-phenylpyrazine is served as a biologically recognizable site. In this study, we synthesized and characterized a novel “3+1” mixed ligand rhenium oxo complex with 2-mercaptoethyl sulfide as a ligand and 3-(4-m-chlorophenyl piperazin1-yl) butane-1-thiol as a biologically active co-ligand. 3-(4-m-Chlorophenyl piperazin-1-yl)butane-1-thiol 4 as a BAM was designed on the basis of prototype 5HT2A serotonin specific antagonist 2 that was originated from ketanserin 1 as its analog. The synthesis of monodentate thiol ligand 4 was planned to achieve by the reductive coupling reaction between 4-mercaptobutane-2-one and 1m-phenylpiperazine. At first, ethyl acetoacetate was protected with ethyleneglycol followed by sequential reactions of ester reduction and tosylation to afford 2-[2-methyl-[1,3]-dioxolane-2yl]ethyl p-toluenesulfonate (5). Tosyl group was replaced by potassium thiolacetate to introduce sulfur that will be ended as binding site to metal. Removal of acetyl group from thiolacetate 6 by carbonate in MeOH did not give the expected free thiol but its dimerized disulfide was formed 7. Then diketone 8 was yielded by treatment of hydrochloric acid in acetone. Reductive cleavage of disulfide at this stage was not quite successful. Instead of reductive amination with two mole equivalents of 1-m-chlorophenylpiperazine coupling