Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood–brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored. We report chemistry for radiolabeling the HDAC inhibitor, panobinostat, with fluoride-18 (compound-1). Like panobinostat, compound 1 retains nanomolar efficacy in diffuse intrinsic pontine glioma (DIPG IV and XIII) cells (IC₅₀ = 122 and 108 nM, respectively), with lesser activity against U87 glioma. With a favorable therapeutic ratio, 1 is highly selective to glioma and demonstrates considerably less toxicity toward healthy astrocyte controls (IC₅₀ = 5265 nM). Compound 1 is stable in aqueous solution at physiological pH (>7 days, fetal bovine serum), and its delivery can be imaged by positron emission tomography (PET). Compound 1 is synthesized in two steps, and employs rapid, late-stage aqueous isotopic exchange ¹⁸F-radiochemistry. PET is used to image the in vivo delivery of [¹⁸F]-1 to the murine central nervous system via convection enhanced delivery.

中文翻译：

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¹⁸ F-放射性标记的Panobinostat允许正电子发射断层扫描术指导组蛋白脱乙酰基酶抑制剂的递送

组蛋白脱乙酰基酶（HDAC）抑制已成为治疗癌症的一种越来越流行的方法，因为HDAC过表达在许多恶性肿瘤中很常见。血脑屏障（BBB）阻止系统递送的药物以有效浓度到达大脑，这使得对脑肿瘤的小分子HDAC抑制特别具有挑战性。为了规避血脑屏障，临床上正在考虑新颖的治疗方法，并且需要能够直接成像其递送的药物，以便可以监测整个血脑屏障的有效递送。我们报告了用氟化物18（化合物1）放射性标记HDAC抑制剂panobinostat的化学方法。像panobinostat一样，化合物1在弥漫性桥脑神经胶质瘤（DIPG IV和XIII）细胞（IC _50分别为122和108 nM）中保留纳摩尔功效，对U87胶质瘤的活性较小。以有利的治疗比率，1对神经胶质瘤具有高度选择性，并且显示出对健康星形胶质细胞对照的毒性大大降低（IC ₅₀ = 5265 nM）。化合物1在生理pH值（> 7天，胎牛血清）中的水溶液中稳定，可以通过正电子发射断层扫描（PET）对其化合物进行成像。化合物1分两步合成，并采用快速的后期水性同位素交换¹⁸ F放射化学。PET用于对[ ¹⁸ F]-1通过对流增强对鼠中枢神经系统的输送。