Design, synthesis, and evaluations of blood-brain barrier permeable ferrocene-conjugated complex ^99mTc-Fc MPP (DO3A) as single photon emission computed tomography imaging neurotracer

Delivery of drugs across natural barriers, especially blood-brain barrier (BBB), has been the focus. Based on the observation that appending organometallic group to drugs facilitates their cellular and BBB permeation, we hypothesize that neuro-receptor-targeted ligands can be made to permeate the BBB using the same approach. The metallocene not only provides a hydrophobic handle for membrane translocation but also facilitates the localization and distribution of the conjugate in the cytoplasm. To test this hypothesis, methoxyphenylpiperazine conjugated ferrocene derivative has been synthesized and evaluated for brain permeability. We have synthesized radiotracer (Fc-MPP-(DO3A)) using ferrocene and 5HT1A antagonist methoxyphenylpiperazine, further conjugated with DO3A, and radiolabeled it with ^99mTc for receptor imaging. At first step, 2-bromoethylamine hydrobromide was protected with di-tert-butyldicarbonate. In the next step, 2-(Boc and ndash; amino)ethyl bromide was conjugated with N-(2-methoxyphenyl)piperazine (MPP). The resulting analog was deprotected using TFA/DCM. Then, the deprotected analog which we get from the last step was conjugated with ferrocenecarboxaldehyde and then it and nbsp; reduced using Pd/C, and further conjugated with DO3A for receptor imaging. The resulting complexes were characterized using various analytical and nbsp; techniques. The yield of the final compound was between 60% and 70%. The compound was purify by column chromatography and characterized by NMR and HRMS. The cytotoxicity of the ^99mTc-MPP(DO3A) complex to HEK cell was and investigated using MTT assay. ^99mTc-Fc MPP(DO3A) was synthesized and used as single photon emission computed tomography imaging neurotracer. In conclusion, this work supports the bioorganometallic conjugation for enhance brain delivery