4-(((4-Iodophenyl)methyl)-4H-1,2,4-triazol-4-ylamino)-benzonitrile: A Potential Imaging Agent for Aromatase,Journal of Medicinal Chemistry

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4-(((4-Iodophenyl)methyl)-4H-1,2,4-triazol-4-ylamino)-benzonitrile: A Potential Imaging Agent for Aromatase
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-10-11 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00849
Jin Song _{1,

2} , Zehui Wu _{1,

2} , Beau Wangtrakuldee ₃ , Seok Rye Choi _{2,

4} , Zhihao Zha ₂ , Karl Ploessl _{2,

4} , Robert H Mach ₂ , Hank Kung _{1,

2,

4}

Affiliation

Aromatase (CYP19) is a rate-limiting enzyme that catalyzes the biosynthesis of estrogens. Imaging agents based on aromatase inhibitors (AIs) have been developed for a PET/SPECT study. A series of compounds was synthesized based on YM511, which has previously been used for breast cancer treatment. Two examples of these derivatives, 4-(((4-iodophenyl)methyl)-4H-1,2,4-triazol-4-yl-amino)-benzonitrile (5) and 4-((1H-imidazol-1-yl)(4-iodobenzyl)amino)benzonitrile (11), displayed potent binding affinities to human aromatase (IC₅₀ = 0.17 and 0.04 nM, respectively). Biodistribution and autoradiographic studies revealed that [¹²⁵I]5 and [¹²⁵I]11 were highly accumulated in the stomach (16.21 and 10.88% dose/g, respectively) and ovaries (8.56 and 3.32% dose/g, respectively) of female rats. Log P of [¹²⁵I]5 was 2.49, meaning good brain penetration. Autoradiograms of brain sections showed a high uptake in the bed nucleus of the stria terminalis and amygdala. These results suggest that [¹²⁵I]5 and [¹²⁵I]11 are potent probes for aromatase imaging in both the brain and peripheral organs.

中文翻译：

4-（（（（4-碘苯基）甲基）-4 H -1,2,4-三唑-4-基氨基）-苄腈：芳香酶的潜在成像剂

芳香酶（CYP19）是一种限速酶，可催化雌激素的生物合成。已经开发出基于芳香酶抑制剂（AIs）的显像剂用于PET / SPECT研究。基于YM511合成了一系列化合物，该化合物先前已用于乳腺癌治疗。这些衍生物的两个例子是4-（（（4-碘苯基）甲基）-4 H -1,2,4-三唑-4-基-氨基）-苄腈（5）和4-（（1 H-咪唑- 1-基）（4-碘苄基）氨基）苯甲腈（11）显示出与人芳香酶的有效结合亲和力（IC _50分别为0.17和0.04 nM）。生物分布和放射自显影研究表明[ ¹²⁵ I] 5和[ ¹²⁵I] 11在雌性大鼠的胃（分别为16.21和10.88％剂量/ g）和卵巢（分别为8.56和3.32％剂量/ g）中高度积累。[ ¹²⁵ I] 5的Log P为2.49，意味着良好的大脑渗透性。大脑切片的放射自显影显示终端纹状体和杏仁核的床核有较高的摄取量。这些结果表明[ ¹²⁵ I] 5和[ ¹²⁵ I] 11是在大脑和周围器官中进行芳香化酶成像的有效探针。

更新日期：2016-10-11

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