Tipre Dnyanesh N, Zoghbi Sami S, Liow Jeih-San, Green Michael V, Seidel Jurgen, Ichise Masanori, Innis Robert B, Pike Victor W
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-0135, USA.
J Nucl Med. 2006 Feb;47(2):345-53.
18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities.
PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis.
PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment.
Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.
18F-FCWAY（18F-反式-4-氟-N-(2-[4-(2-甲氧基苯基)哌嗪-1-基]乙基)-N-(2-吡啶基)环己烷甲酰胺）在正电子发射断层扫描（PET）临床研究中可用于测量人类受试者脑区的5-羟色胺1A（5-HT1A）受体密度，但由于脱氟作用，其在骨骼中有显著的放射性摄取。颅骨中的放射性摄取会因放射性通过部分容积效应的溢出而影响相邻脑区5-HT1A受体密度测量的准确性。我们的目的是通过大鼠模型证明，18F-FCWAY的脱氟作用在体内可能受到抑制，从而提高其在测量脑区5-HT1A受体密度方面的适用性。
给予18F-FCWAY后对大鼠头部进行PET检查，以确认脑中测量到的放射性分布主要由与5-HT1A受体的结合所主导，并揭示18F-FCWAY在体内的脱氟程度，以颅骨中放射性（18F-氟离子）摄取来表示。西咪替丁、双氯芬酸和咪康唑是已知的细胞色素P450 2EI抑制剂，在体外对大鼠肝微粒体中18F-FCWAY脱氟作用的抑制能力进行了测试。通过PET和静脉血分析评估咪康唑对大鼠的治疗对颅骨放射性摄取的影响，以及进而对脑5-HT1A受体成像的溢出影响。
PET证实了18F-FCWAY作为大鼠脑内5-HT1A受体放射性配体的潜力，同时也揭示了广泛的脱氟现象。在体外大鼠肝微粒体中，咪康唑几乎完全抑制了18F-FCWAY的脱氟作用，双氯芬酸的抑制作用较小。在PET实验中，在给予18F-FCWAY前45分钟内静脉注射硝酸咪康唑（60毫克/千克）对大鼠进行治疗，几乎消除了脱氟作用和放射性在骨骼中的摄取。此外，脑放射性几乎增加了一倍，而富含受体的腹侧海马体中的放射性与受体较少的小脑的放射性之比几乎增加了两倍，达到14。咪康唑治疗还延长了放射性配体的血浆半衰期。
咪康唑治疗通过消除18F-FCWAY的脱氟作用，实现了大鼠脑5-HT1A受体的有效成像。在咪康唑治疗的大鼠中进行18F-FCWAY PET可作为研究神经精神疾病或药物作用的啮齿动物模型中5-HT1A受体的有效平台。
