Synthesis of a benzoxazinthione derivative of tanaproget and pharmacological evaluation for PET imaging of PR expression
Synthesis of a benzoxazinthione derivative of tanaproget and pharmacological evaluation for PET imaging of PR expression
复制标题
DOI：
10.1186/s41181-018-0054-z
复制
发表时间：
2019-01-10
影响因子：
4.6
通讯作者：
Smith, Graham
中科院分区：
文献类型：
--
作者：
Allott, Louis;Miranda, Cecilia;Smith, Graham
背景乳腺癌活检组织中雌激素受体（ER）和孕激素受体（PR）表达的组织学评估可以对患者进行内分泌治疗分层。此外，PR表达可以预测选择性雌激素受体调节剂（SERMs）的应答。目前用于PR检测的免疫组织化学方法受到与活检相关的采样误差和缺乏标准化方案的限制；正电子发射断层扫描（PET）使用受体靶向放射性药物提供定量的全身成像可以克服这些限制。PR的表达已在临床应用PET成功成像，然而，研究具有改善药代动力学和代谢稳定性的新放射配体是可取的。结果我们报道了一个非甾体PR配体库的合成，这些配体被评估为PET放射性配体。选择了具有低纳摩尔活性的先导候选物（[F-18]2）并进行了放射性标记，其放射化学产率为2.292.31%（衰变校正），放射化学纯度（RCP）为>95%，摩尔活性为2.5 +/- 1.6GBq/mu mol。细胞摄取研究表明，与MDA-MB-231 （PR-）对照相比，[F-18]2在T47D （PR++）乳腺癌细胞中具有显著的特异性积累；然而，体内评价被放射性配体的快速去氟化所混淆。MLM中2的体外代谢物分析证实了质谱法的脱氟和硫代氨基甲酸酯到氧代氨基甲酸酯部分的氧化代谢。结论建立了一条获得[F-18]2的途径，尽管其放射化学产率低，摩尔活性适中，但可以进行体外和体内评价。[F-18]2在PR++ T47D细胞中表现出选择性摄取，可被黄体酮以剂量依赖性方式阻断。然而，[F-18]2在成像方案的时间框架内表现出较差的体内代谢稳定性和快速去氟。
BackgroundThe histological evaluation of estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer lesions from biopsy tissue can stratify patients to receive endocrine therapy. Furthermore, PR expression can predict response to selective estrogen receptor modulators (SERMs). Current immunohistochemical approaches to PR detection are limited by sampling error associated with biopsy and lack of standardised protocols; positron emission tomography (PET) using receptor targeted radiopharmaceuticals to provide quantitative, whole-body imaging may overcome these limitations. PR expression has been successfully imaged with PET in the clinical setting, however investigation into new radioligands with improved pharmacokinetics and metabolic stability is desirable.ResultsWe report the synthesis of a focused library of non-steroidal PR ligands evaluated for use as PET radioligands. A lead candidate ([F-18]2) with low nanomolar activity was selected and radiolabelled with a radiochemical yield of 2.292.31% (decay-corrected), radiochemical purity (RCP) >95% and a molar activity of 2.5 +/- 1.6GBq/mu mol. Cell uptake studies showed a significant and specific accumulation of [F-18]2 in T47D (PR++) breast cancer cell compared to MDA-MB-231 (PR-) control; however, in vivo evaluation was confounded by rapid defluorination of the radioligand. In vitro metabolite analysis of 2 in MLM confirmed defluorination and oxidative metabolism of the thiocarbamate to oxocarbamate moiety by mass spectrometry.ConclusionsA route to access [F-18]2 was developed to allow in vitro and in vivo evaluation, albeit with low radiochemical yield and modest molar activity. [F-18]2 demonstrated selective uptake in PR++ T47D cells which could be blocked in a dose dependent manner with progesterone. However, [F-18]2 showed poor in vivo metabolic stability with rapid defluorination within the time frame of the imaging protocol.