Pretherapy 124I-MIBG Dosimetry for Planning 131I-MIBG Neuroblastoma Therapy

描述（申请人提供）：神经母细胞瘤是儿童最常见的颅外恶性实体瘤。虽然常规治疗方案通常在早期阶段就能治愈，但对于很大比例的患者，特别是对常规治疗产生耐药性的患者来说，晚期疾病仍然是致命的。MIBG通过一种特殊的去甲肾上腺素转运体（NET）被交感神经元吸收，90%的神经母细胞瘤肿瘤是MIBG阳性的。因此，当MIBG被131I标记时，131I-MIBG成为靶向放射性核素治疗神经母细胞瘤的药物。131I-MIBG是一种放射治疗β粒子的放射性核素，其物理半衰期相对较长（8.02天）。对于131i - mibg治疗，个体化辐射剂量测定可以通过使用不同放射性碘（如I-123）的相同示踪剂进行治疗前成像来实现。I-123是伽马照相机和SPECT的首选显像剂；但它的半衰期比I-131相对较短（13.2小时对8.02天），因此在几天内跟踪123I-MIBG患者的全部过程并不简单，而且在技术上具有挑战性。相反，另一种放射性碘，I-124的半衰期（4.2天）与I-131的半衰期更接近，并且可以通过PET成像，被认为在定量上比SPECT更准确。我们的目标是使用124I-MIBG PET/CT作为个体化的131I-MIBG放疗处方工具，以实现肿瘤的最佳治疗和对放射敏感器官的最小辐射剂量。由于124I-MIBG尚未用于儿童的这一适应症（尽管124I-MIBG已用于有限数量的成人），因此应在其用于人类之前进行精心设计的临床前研究，并进行辐射剂量估计的终点。我们的具体目标是：目的1：利用神经母细胞瘤动物模型确定124I-MIBG在肿瘤和体内正常器官中的分布。将在4天内的多个时间点进行124I-MIBG小动物PET/CT检查，分析成像数据，研究肿瘤及其他器官的药代动力学。目的2：根据临床前124I-MIBG成像数据，计算不同患者大小范围内儿童人体等效有效辐射剂量。为此，我们的目标是估计124I-MIBG的正常器官剂量，以确保安全性，而不是专门针对131I-MIBG的治疗处方。我们将申请IND，并将准备人体成像作为这一目标的一部分。目的3：评估儿童124I-MIBG PET/CT对计划接受131I-MIBG治疗的神经母细胞瘤患者肿瘤和器官剂量测定的可行性。我们将开发一种患者特异性剂量学计算工具，可用于131I-MIBG的剂量处方。辐射剂量的估计将集中在确定有效地向肿瘤细胞提供治疗剂量所需的最佳活性，同时将正常器官的辐射剂量保持在可接受的水平。将131I-MIBG治疗的个体化处方的结果与治疗结果进行描述性比较，特别是原发肿瘤缩小的结果。

DESCRIPTION (provided by applicant): Neuroblastoma is the most common extracranial malignant solid tumor in children. Although the conventional treatment options are often curative at early stages, advanced disease remains fatal for a large percentage of patients, particularly for those who become resistant to conventional therapy. MIBG is taken up by sympathetic neurons via a specific norepinephrine transporter (NET) and 90% of all neuroblastoma tumors are MIBG-avid. Thus, when MIBG is labeled with 131I, a radionuclide that emits therapeutic beta particles with a relatively long physical half-life (8.02 days), 131I-MIBG becomes an agent for targeted radionuclide therapy of neuroblastoma. For the treatment with131I-MIBG, individualized radiation dosimetry can be achieved by pretherapy imaging using the same tracer with a different radioiodine such as I-123. I-123 is a favored imaging agent using gamma camera and SPECT; but it has a relatively shorter half-life than that of I-131 (13.2 hours versus 8.02 days) so that following the full time course of 123I-MIBG behavior in patients over a few days is not straightforward, and technically challenging. Instead, another radioiodine, I-124 has a closer half-life (4.2 days) to that of I-131, and can be imaged by PET that is considered quantitatively more accurate than SPECT. Our goals are to use 124I-MIBG PET/CT as an individualized 131I-MIBG radiotherapy prescription tool to achieve optimal treatment of tumors and minimal radiation dose to radiosensitive organs. Since 124I-MIBG has not been used in children for this indication (although 124I-MIBG was used in a limited number of adults), carefully designed preclinical studies with end points of radiation dose estimations should proceed before its human use. Our specific aims are: Aim 1: To determine the distribution of 124I-MIBG in tumors and normal organs in vivo using animal models of neuroblastoma. Small animal PET/CT with 124I-MIBG will be performed at multiple time points over four days, and the imaging data will be analyzed to study pharmacokinetics in tumors and other organs. Aim 2: To calculate the pediatric human-equivalent effective radiation dose in the range of patient sizes from preclinical 124I-MIBG imaging data. For this aim, our goal is to estimate the normal organ doses with 124I-MIBG to ensure safety, not specifically intended for 131I-MIBG treatment prescription. We will apply for the IND, and will prepare for human imaging as a part of this aim. Aim 3: To assess the feasibility of tumor and organ dosimetry with pediatric 124I-MIBG PET/CT in selected neuroblastoma patients who are scheduled for 131I-MIBG treatment. We will develop a patient-specific dosimetry calculation tool that will be available for the dose prescription of 131I-MIBG. Estimations of radiation dose will be focused on the determination of optimal activity needed to effectively deliver therapeutic dose to tumor cells while keeping radiation dose to normal organs at an acceptable level. The outcomes of the individualized prescription of the 131I-MIBG treatment will be descriptively compared to the therapy outcomes, particularly the primary tumor size reduction.