CEP-32496, also known as RXDX-105 or Agerafenib, is a new orally active inhibitor for the mutated v-raf murine sarcoma viral oncogene homolog B1 (BRAFV600E), which has attracted considerable attention in clinical trials for the treatment of human cancers. Here, we used carbon-11-labeled CEP-32496 ([11C]CEP-32496) as a positron emission tomography (PET) radiotracer to evaluate its pharmacokinetic properties and explore its potential for in vivo imaging. Following radiotracer synthesis, we performed in vitro binding assays and autoradiography of [11C]CEP-32496 in the A375 melanoma cell line and on tumor tissue sections from mice harboring the BRAFV600E mutation. These were followed by PET scans and biodistribution studies on nude mice bearing subcutaneous A375 cell-induced melanoma. [11C]CEP-32496 showed high binding affinity for BRAFV600E-positive A375 melanoma cells and densely accumulated in the respective tissue sections; this could be blocked by the BRAFV600E selective antagonist sorafenib and by unlabeled CEP-32496. The PET and biodistribution results revealed that [11C]CEP-32496 accumulated continuously but slowly into the tumor within a period of 0 to 60 minutes postinjection in A375-melanoma-bearing nude mice. Metabolite analysis showed high in vivo stability of [11C]CEP-32496 in plasma. Our results indicate that [11C]CEP-32496 has excellent specificity and affinity for the BRAFV600E mutation in vitro, while its noninvasive personalized diagnostic role needs to be studied further.

中文翻译：

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[11C] CEP-32496在带有BRAFV600E突变诱发的黑素瘤的裸鼠中的药代动力学评估。

CEP-32496，也称为RXDX-105或Agerafenib，是突变的v-raf鼠肉瘤病毒致癌基因同系物B1（BRAFV600E）的新型口服活性抑制剂，在治疗人类癌症的临床试验中引起了极大的关注。在这里，我们使用碳11标记的CEP-32496（[11C] CEP-32496）作为正电子发射断层扫描（PET）放射性示踪剂，以评估其药代动力学特性并探索其在体内成像中的潜力。放射性示踪剂合成后，我们在A375黑色素瘤细胞系中以及来自携带BRAFV600E突变小鼠的肿瘤组织切片上进行了[11C] CEP-32496的体外结合测定和放射自显影。随后，对携带皮下A375细胞诱导的黑色素瘤的裸鼠进行PET扫描和生物分布研究。[11C] CEP-32496对BRAFV600E阳性A375黑色素瘤细胞显示出高结合亲和力，并在各个组织切片中密集堆积；BRAFV600E选择性拮抗剂索拉非尼和未标记的CEP-32496可以阻止这种情况。PET和生物分布结果表明[11C] CEP-32496在带有A375黑色素瘤的裸鼠注射后0至60分钟内连续但缓慢地积累到肿瘤中。代谢物分析显示[11C] CEP-32496在血浆中具有很高的体内稳定性。我们的结果表明，[11C] CEP-32496在体外对BRAFV600E突变具有极好的特异性和亲和力，而其无创个性化诊断作用还需要进一步研究。BRAFV600E选择性拮抗剂索拉非尼和未标记的CEP-32496可以阻止这种情况。PET和生物分布结果表明[11C] CEP-32496在带有A375黑色素瘤的裸鼠注射后0至60分钟内连续但缓慢地积累到肿瘤中。代谢物分析显示[11C] CEP-32496在血浆中具有很高的体内稳定性。我们的结果表明，[11C] CEP-32496在体外对BRAFV600E突变具有极好的特异性和亲和力，而其无创个性化诊断作用还需要进一步研究。BRAFV600E选择性拮抗剂索拉非尼和未标记的CEP-32496可以阻止这种情况。PET和生物分布结果表明[11C] CEP-32496在带有A375黑色素瘤的裸鼠注射后0至60分钟内连续但缓慢地积累到肿瘤中。代谢物分析显示[11C] CEP-32496在血浆中具有很高的体内稳定性。我们的结果表明，[11C] CEP-32496在体外对BRAFV600E突变具有极好的特异性和亲和力，而其无创个性化诊断作用还需要进一步研究。代谢物分析显示[11C] CEP-32496在血浆中具有很高的体内稳定性。我们的结果表明，[11C] CEP-32496在体外对BRAFV600E突变具有出色的特异性和亲和力，而其无创个性化诊断作用还需要进一步研究。代谢物分析显示[11C] CEP-32496在血浆中具有很高的体内稳定性。我们的结果表明，[11C] CEP-32496在体外对BRAFV600E突变具有极好的特异性和亲和力，而其无创个性化诊断作用还需要进一步研究。