SYNTHESIS OF 11-BETA-[F-18]FLUORO-5-ALPHA-DIHYDROTESTOSTERONE AND 11-BETA-[F-18]FLUORO-19-NOR-5-ALPHA-DIHYDROTESTOSTERONE - PREPARATION VIA HALOFLUORINATION-REDUCTION, RECEPTOR-BINDING, AND TISSUE DISTRIBUTION
SYNTHESIS OF 11-BETA-[F-18]FLUORO-5-ALPHA-DIHYDROTESTOSTERONE AND 11-BETA-[F-18]FLUORO-19-NOR-5-ALPHA-DIHYDROTESTOSTERONE - PREPARATION VIA HALOFLUORINATION-REDUCTION, RECEPTOR-BINDING, AND TISSUE DISTRIBUTION
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DOI：
10.1021/jm00005a009
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发表时间：
1995-03-03
影响因子：
7.3
通讯作者：
KATZENELLENBOGEN, JA
中科院分区：
文献类型：
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作者：
CHOE, YS;LIDSTROM, PJ;KATZENELLENBOGEN, JA
我们制备了 11 β-氟-5 α-二氢睾酮 (11 β-F-DHT, 1) 和 11 β-氟-19-nor-5 α-二氢睾酮 (11 β-F-19-nor-DHT, 2)，以研究这些用氟 18 标记的新雄激素作为潜在的基于雄激素受体 (AR) 的前列腺癌成像剂的特性。这些化合物分别由氢化可的松经 6 个步骤合成，由 1,4-雄甾二烯-3,11,17-三酮经 13 个步骤合成。 11β-F-DHT 和 11β-F-19-nor-DHT 与 AR 的相对结合亲和力 (RBA) 分别为 53.1 和 75.3 (R1881 = 100)，后者是氟取代雄激素中报道最高的。氟化步骤涉及在 9(11)-双键上添加卤素氟化物，然后在 9 α 位进行还原脱卤，已进行了调整，以在 DHT 和 19-nor-DHT 的 11 β 位引入氟 18 标记。使用己烯雌酚预处理的成熟雄性大鼠，在组织分布研究中对两种高亲和力 F-18 标记的配体 [F-18]-1 和 [F-18]-2 进行了体内评估。 11β-F-DHT 显示高前列腺摄取和选择性前列腺与血液和前列腺与肌肉摄取比率，后两个比率从注射后 1 小时的 5 和 8 增加到注射后 4 小时的 12 和 19。此外，该化合物在骨中的吸收率较低，在迄今为止测试的所有用氟 18 标记的雄激素中表现出最低的体内脱氟作用。因此，11β-F-DHT 在大鼠体内的体内特性有利于前列腺癌的成像。另一方面，11β-F-19-去甲-DHT 显示前列腺摄取低、选择性低，而肝脏、肾脏和膀胱摄取高。尽管该配体具有最高的 RBA 并且很少发生代谢脱氟，但它似乎在体内代谢快速。因此，很明显，雄激素的生物分布特性受到其结构和代谢以及 RBA 的影响。
We have prepared 11 beta-fluoro-5 alpha-dihydrotestosterone (11 beta-F-DHT, 1) and 11 beta-fluoro-19-nor-5 alpha-dihydrotestosterone (11 beta-F-19-nor-DHT, 2) in order to investigate the properties of these new androgens labeled with fluorine-18 as potential androgen receptor (AR)-based imaging agents for prostate cancer. These compounds were synthesized in 6 steps from hydrocortisone and in 13 steps from 1,4-androstadiene-3,11,17-trione, respectively. Relative binding affinities (RBA) of 11 beta-F-DHT and 11 beta-F-19-nor-DHT to AR are 53.1 and 75.3 (R1881 = 100), respectively, the latter being the highest reported among fluorine-substituted androgens. The fluorination step, which involves addition of halogen fluoride across the 9(11)-double bond, followed by reductive dehalogenation at the 9 alpha-position has been adapted to introduce a fluorine-18-label at the 11 beta-position of DHT and 19-nor-DHT. The two high-affinity F-18-labeled ligands [F-18]-1 and [F-18]-2 were evaluated in vivo, in tissue distribution studies using diethylstilbestrol-pretreated mature male rats. 11 beta-F-DHT shows high prostate uptake and selective prostate to blood and prostate to muscle uptake ratios, the latter two ratios increasing from 5 and 8 at 1 h to 12 and 19 at 4 h postinjection. Moreover, this compound has low uptake in bone, displaying the lowest in vivo defluorination among all androgens labeled with fluorine-18 tested so far. The in vive properties of 11 beta-F-DHT in rats are thus favorable for imaging of prostate cancer. On the other hand, 11 beta-F-19-nor-DHT shows low prostate uptake with low selectivity and high uptake in liver, kidney, and bladder. Even though this ligand has the highest RBA and undergoes little metabolic defluorination, it appears to suffer from rapid metabolism in vivo. Therefore, it is apparent that the biodistribution properties of androgens are affected by their structure and metabolism as well as by their RBA.