<i>N</i>′‑3-(Trifluoromethyl)phenyl Derivatives of <i>N</i>‑Aryl‑<i>N</i>′‑methylguanidines as Prospective PET Radioligands for the Open Channel of the <i>N</i>‑Methyl‑d‑aspartate (NMDA) Receptor: Synthesis and Structure–Affinity Relationships

N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer’s disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated “open channel” state would be useful for research on such disorders and for the development of novel therapies. To date, no radioligands have shown well-validated efficacy for imaging NMDA receptors in human subjects. In order to discover improved radioligands for PET imaging, we explored structure–affinity relationships in N′-3-(trifluoromethyl)­phenyl derivatives of N-aryl-N′-methylguanidines, seeking high affinity and moderate lipophilicity, plus necessary amenability for labeling with a positron-emitter, either carbon-11 or fluorine-18. Among a diverse set of 80 prepared N′-3-(trifluoromethyl)­phenyl derivatives, four of these compounds (13, 19, 20, and 36) displayed desirable low nanomolar affinity for inhibition of [3H]­(+)-MK801 at the PCP binding site and are of interest for candidate PET radioligand development.N-甲基-D-天冬氨酸（N-Methyl-d-aspartate, NMDA）受体功能异常已被证实与多种神经精神疾病相关，包括阿尔茨海默病、癫痫、药物成瘾及精神分裂症。可借助正电子发射断层显像（PET）成像并量化人类大脑处于激活“开放通道”状态的NMDA受体的放射性配体，对这类疾病的研究及新型疗法的开发具有重要应用价值。截至目前，尚未有放射性配体在人类受试者中针对NMDA受体成像方面展现出经过充分验证的成像效能。为发掘可用于PET成像的更优放射性配体，本研究针对N-芳基-N′-甲基胍类的N′-3-(三氟甲基)苯基衍生物开展结构-亲和力关系探究，旨在获得高亲和力、适中脂溶性，且具备可被碳-11（carbon-11）或氟-18（fluorine-18）这类正电子发射体标记的可行性。在合成的80种结构多样的N′-3-(三氟甲基)苯基衍生物中，有4种化合物（13、19、20及36）对苯环利定（Phencyclidine, PCP）结合位点处[³H]-(+)-MK801的抑制活性展现出理想的纳摩尔级低亲和力，有望作为候选PET放射性配体进行开发。