Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]fluoroestradiol-17β and 16β-[18F]fluoromoxestrol in isolated hepatocytes
Comparative breast tumor imaging and comparative in vitro metabolism of 16α-[18F]fluoroestradiol-17β and 16β-[18F]fluoromoxestrol in isolated hepatocytes
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DOI：
10.1016/s0969-8051(98)00079-1
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发表时间：
1999-01-01
影响因子：
3.1
通讯作者：
Welch, MJ
中科院分区：
文献类型：
--
作者：
Jonson, SD;Bonasera, TA;Welch, MJ
16 beta-[F-18]Fluoromoxestrol（[F-18]beta FMOX）是16 alpha-[F-18]fluoroestradiol-17 beta（[F-18]FES）的类似物，FES是一种放射性药物，已知是雌激素受体阳性（ER+）人类乳腺肿瘤的有效正电子发射断层扫描（PET）成像剂。基于在大鼠模型中靶组织摄取效率和选择性的比较，预测[F-18] β FMOX作为显像剂与[F-18]FES一样有效。然而，在12名患者（其中3名患有ER+乳腺癌）的[F-18] β FMOX初步PET成像研究中，未观察到[F-18] β FMOX的肿瘤定位。为了寻找[F-18]beta FMOX临床试验失败的原因，我们检测了[F-18]beta FMOX和[F-18]FES在离体大鼠、狒狒和人肝细胞中的代谢率。我们还研究了血清蛋白性激素结合球蛋白（SHBG）对这些代谢率的影响，SHBG与[F-18]FES的结合优于[F-18] β FMOX。未成熟大鼠肝细胞代谢[F-18]FES的速度比[F-18]beta FMOX快31倍，而成熟大鼠细胞代谢[F-18]FES的速度仅为3倍，狒狒和人肝细胞代谢[F-18]beta FMOX的速度仅为2倍。在存在SHBG的情况下，[F-18]FES在成熟大鼠肝细胞中的代谢消耗率降低了26%。因此，在大鼠中测定的[F-18] β FMOX非常有利的靶组织摄取特征可能是由于其在该种属中对代谢（相对维斯[F-18]FES）的相对抗性，这一优势强烈反映在大鼠肝细胞中的相对代谢率中。在狒狒和人类中，[F-18]FES与蛋白质广泛结合，并受到代谢保护，这种作用可能在一定程度上反映为相对于[F-18] β FMOX，该化合物在狒狒和人类肝细胞中的代谢速率降低。因此，在灵长类动物中，SHBG可能通过选择性地保护该配体免于代谢并确保其递送至含受体的细胞来增强ER+肿瘤中ER介导的[F-18]FES摄取。除了目前的F-18雌激素筛选方法，包括评估体内ER介导的摄取在未成熟的雌性大鼠，研究比较新的受体配体的代谢在分离的肝细胞，特别是那些从灵长类动物或人类，可能有助于预测这些配体的潜力，为人类PET成像。核医学生物学26;1：123-130，1999。(C)1998年爱思唯尔科学公司
16 beta-[F-18]Fluoromoxestrol ([F-18]beta FMOX) is an analog of 16 alpha-[F-18]fluoroestradiol-17 beta ([F-18]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [F-18]beta FMOX was predicted to be as effective an imaging agent as [F-18]FES. However, in a preliminary PET imaging study with [F-18]beta FMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [F-18]beta FMOX was observed. In search for an explanation for the unsuccessful [F-18]beta FMOX clinical trial, we have examined the rate of metabolism of [F-18]beta FMOX and [F-18]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [F-18]FES better than [F-18]beta FMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [F-18]FES 31 times faster than [F-18]beta FMOX, whereas mature rat cells metabolized [F-18]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [F-18]beta FMOX. In the presence of SHBG, the metabolic consumption rate for [F-18]FES in mature rat hepatocytes decreased by 26% Thus, the very favorable target tissue uptake characteristics of [F-18]beta FMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [F-18]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [F-18]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [F-18]beta FMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [F-18]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor containing cells. In addition to current screening methods for F-18 estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging. NUCL MED BIOL 26;1:123-130, 1999. (C) 1998 Elsevier Science Inc.