Global Drug Discovery, Bayer Healthcare, Berlin, Germany, Muellerstrasse 178, 13342, Berlin, Germany,
Eur J Nucl Med Mol Imaging. 2014 Jan;41(1):89-101. doi: 10.1007/s00259-013-2527-3. Epub 2013 Aug 17.
Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[(18)F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel (18)F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor.
The (18)F-radiolabelled stereoisomers of 2-[(18)F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553.
BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 mSv/MBq. Non-clinical safety studies did not show off-target activity, effects on vital organs function or dose-dependent adverse effects.
BAY 1075553 was identified as a promising PET tracer for PSMA-positive prostate tumours in preclinical studies. BAY 1075553 can be produced using a robust, direct radiosynthesis procedure. Pharmacokinetic, toxicology and safety pharmacology studies support the application of BAY 1075553 in a first-in-man microdose study with single i.v. administration.
前列腺特异性膜抗原（PSMA）在前列腺癌中过度表达，因此被作为诊断和分期疾病的生物标志物进行研究。在这里，我们报告了一种新型（18）F 标记的 PSMA 酶活性小分子抑制剂 BAY 1075553（（2S，4S）-和（2R，4S）-2-[(18)F]氟-4-膦酸基甲基戊二酸的 9:1 混合物）的临床前数据，该抑制剂可从直接放射性标记前体高效合成。
通过其各自的立体纯前体二甲基 2-[[双（苄氧基）膦酰基]甲基]-4-（对甲苯磺酰氧基）戊二酸，合成了 2-[(18)F]氟-4-（膦酸基甲基）戊二酸的（18）F 放射性标记对映异构体。在携带 LNCaP、22Rv1 和 PC-3 肿瘤的小鼠中进行了体内正电子发射断层扫描（PET）成像和生物分布研究。基于啮齿动物的生物分布研究，计算了药代动力学参数和剂量估计值。为了支持单次人微剂量研究的非临床安全性评估（安全药理学、毒理学），使用非放射性外消旋类似物 BAY 1075553 进行了体外的脱靶效应、对重要器官功能的影响（狗的心血管、大鼠的神经系统）、致突变筛选和大鼠的单次剂量延长研究。
BAY 1075553 在 PSMA 阳性肿瘤荷瘤小鼠中表现出高肿瘤积聚，优于其他测试的立体异构体。BAY 1075553 的快速清除导致除肾脏和膀胱外的其他器官的背景信号较低，这主要是由于 BAY 1075553 的肾脏消除所致。观察到少量的骨骼摄取，随着时间的推移减少，表明是器官特异性摄取，而不是 BAY 1075553 在体内的脱氟。生物分布研究发现肾脏和膀胱壁的器官剂量最高，导致人类的预期有效剂量（ED）为 0.0219 mSv/MBq。非临床安全性研究未显示出脱靶活性、对重要器官功能的影响或剂量依赖性不良反应。
BAY 1075553 被确定为临床前研究中 PSMA 阳性前列腺肿瘤的有前途的 PET 示踪剂。BAY 1075553 可以使用稳健、直接的放射合成程序生产。药代动力学、毒理学和安全药理学研究支持 BAY 1075553 在单次静脉注射给药的首次人体微剂量研究中的应用。
