吡啶基取代之1-[2-(二苯基甲氧基)乙基]-4-(3-苯丙基)哌嗪衍生物的合成及生物活性研究

Abstract

To develop the 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine (GBR12935) derivatives as a novel potential positron emission tomography (PET) imaging agents for dopamine transporter (DAT), a series of pyridyl-substituted derivatives was synthesized. In the series, except for the m-pyridyl substituted derivatives, all other derivatives possessed high binding affinity for DAT (Ki = 8.01–22.0 nM). The substitution of one of the phenyl ring for pyridine in GBR12935 analogs significantly reduces the lipophilicity of these compounds from log D7.4 value of 4.1 to 3.6. Introduction of fluorine atom next to the nitrogen atom in the pyridine ring, such as compounds 15a–c, increased the log D value of the compounds to 4.4. All compounds showed good blood brain barrier (BBB) penetration ability with a Pe (10-6 cm/s) values range from 31 to 89. Among this series, compound 19a showed the highest DAT binding affinity as well as appropriate lipophilicity and favorable brain penetration ability (Ki = 8.01 nM, Log D = 3.74, Pe = 62×10-6 cm/s), and is the candidate for the further development to be a novel DAT PET radiotracers.