NMR DETECTION OF 13C-TEMOZOLOMIDE IN CANINE BRAIN TUMORS

描述（改编自申请人摘要）：拟定的目的 研究的目的是确定监测药物的药代动力学的可行性， 13 C-标记的药物[3- 13 C]替莫唑胺（TMZ）通过NMR光谱在大的 临床剂量水平的动物模型。研究将在 成年比格犬和具有自发脑的犬中的可移植性胶质瘤 肿瘤的初步研究已经证明， 用选择性~（13）C极化转移光谱监测[3-~（13）C]TMZ 皮下RIF-1肿瘤的小鼠在给予 是临床剂量200 mg/m2的25倍（5.91 mg/kg）。拟定研究 将确定进行临床试验的可行性， 人类实验对象替莫唑胺目前处于II期临床试验阶段， 显示出对人类脑肿瘤和黑色素瘤的有希望的活性。拟议 研究采用替莫唑胺作为原型，以测试使用的一般概念 13 C-标记作为监测它们的方法的抗肿瘤剂 通过NMR光谱法测定药代动力学。这种方法将有助于 根据个别病人的需要量身定做化疗方案 并在早期阶段可靠地识别无反应的患者， 化疗，从而节省他们不必要的毒性和费用。第一 本项目的目的是确定检测的最佳方法 [3-13CJTMZ.将在体模和犬上评价四种方法， 在4.7T/50 cm动物光谱仪上的可移植胶质瘤：1）选择性 从1H到13 C的偏振转换，检测13 C，6 2）反向 极化从13 C转换到1H，检测1H，42 3）梯度回波 13 C到1H的异质多量子相干转移及其探测 4）质子观察碳去耦光谱。5这些方法将是 比较灵敏度、功率沉积和运动灵敏度。 根据这些研究选择的方法将在临床上实施。 1.5 T和4 T扫描仪，用于监测[3- 13 C]TMZ在 患有可移植神经胶质瘤和自发性脑瘤的狗。标记药物 将由申请人进行综合，他们已经制定了一个更有效， [3- 13 C]TMZ的合成方法比已报道的方法更经济， literatue.33

DESCRIPTION (Adapted from applicant's abstract): The purpose of the proposed study is to determine the feasibility of monitoring the pharmacokinetics of a 13C-labeled drug [3-13C]temozolomide (TMZ) by NMR spectroscopy in a large animal model at clinical dose levels. Studies will be performed on transplantable gliomas in adult beagles and in dogs with spontaneous brain tumors. Preliminary studies have already demonstrated the feasibility of monitoring [3-13C]TMZ by selective 13C polarization transfer spectroscopy in mice with subcutaneous RIF-1 tumors at 9.4 after administration of doses that were 25 times the clinical dose of 200 mg/m2 (5.91 mg/kg). The proposed study will determine the feasibility of undertaking clinical trials of this method in human subjects. Temozolomide is currently in Phase II clinical trials and has shown promising activity against human brain tumors and melanomas. The proposed study employs temozolomide as a prototype to test the general concept of using 13C-labeling of antineoplastic agents as a method for monitoring their pharmacokinetics by NMR spectroscopy. This method would facilitate tailor-fitting of chemotherapy schedules to the needs of individual patients and reliably identifying nonresponsive patients at an early stage of chemotherapy, thereby sparing them unnecessary toxicity and expense. The first objective of this project is to determine the optimum method for detecting [3-13CJTMZ. Four methods will be evaluated on phantoms and on dogs with transplantable gliomas on a 4.7T/50 cm animal spectrometer: 1) selective polarization transfer from 1H to 13C with detection of 13C, 6 2) inverse polarization transfer from 13C to 1H with detection of 1H, 42 3) gradient echo heteronuclear multiple quantum coherence transfer from 13C to 1H with detection of 1H, 4 4) proton observe carbon decouple spectroscpy.5 These methods will be compared with respect to sensitivity, power deposition and motion sensitivity. The method chosen on the basis of these studies will be implemented on clinical 1.5 T and 4T scanners and used to monitor the pharmacokinetics of [3-13C]TMZ in dogs with transplantable gliomas and spontaneous brain tumors. The labeled drug will be synthesized by the applicants, who have developed a more efficient and economical method of synthesis of [3-13C]TMZ than had been reported in the literatue.33