Development of Tumor Proliferation PET Tracer FLT using a Low Cost Single Dose Automatic Production and Quality Control Biomarker Generator System

 描述（由申请人提供）：在世界范围内，每5秒就有一人死于癌症。正电子发射断层扫描（PET）是一种有效的工具，在诊断癌症和监测治疗效果方面至关重要。PET成像依赖于短寿命放射性同位素的使用。最常用的放射性示踪剂[18F]FDG的商业分销已在美国、西欧和日本覆盖了80%的患者人群。然而，“新兴世界”（约占世界人口的85%）仍然无法随时获得[18F]FDG。ABT Molecular Imaging，Inc. (ABT)致力于增加美国和全球PET的使用。该公司专有的“按需剂量（tm）”生物标记发生器（BG）大大简化了[18F]FDG的生产。它还减少了医疗机构将PET诊断引入新地区所需的投资。然而，对PET相关技术的需求仍然存在. [18F]FDG生物标志物并不是成功诊断/治疗监测癌症所需的唯一生物标志物。[18F]FLT已被证明可提供[18F]FDG在一系列癌症中肿瘤增殖的补充信息，占所有现有病例的72%（见Comm. Plan Section A），但其成本为3000 - 4000美元/剂。[18F]FLT已经显示出如此多的前景，以至于美国国家癌症研究所为[18F]FLT制定了IND（11/2004），以积极鼓励研究人员交叉申请（有350多项临床试验）。此处提议的快速通道SBIR项目将提供开发和验证ABT自动合成和执行[18 F]FLT自动QC检测的能力所需的资金，在ABT支持下简化研究中心IND提交。设想的ABT系统将使用可在[18 F]FDG剂量之间使用的一次性剂量合成卡以约250美元/剂量产生[18 F]FLT。整合[18 F]FLT的挑战是（1）生产足够的F-18以说明[18 F]FLT的合成产率，（2）自动合成，以及（3）在BG系统上自动进行[18 F]FLT的QC测试。对于这个快速通道，ABT的PI，Khachaturian博士，将领导一个由12人组成的专家研发团队，追求3个第一阶段和3个第二阶段目标：（目标1）研究将回旋加速器产生的[18 F]量从1增加到1.7 [mCi/min]的可行性;（目标2）用美国和欧盟前体生产一个单位剂量的[18 F]FLT（2.0-3.6 [mL]，2.5-5 [mCi]）;和（目标3）通过美国和欧盟药典质量控制测试。第I阶段验证将全面确认概念验证，因此第II阶段开发可专注于确保一致的[18 F]FLT产量和生产质量。第二阶段的目标是：（目标4）对于n = 4个目标和20次运行/目标，F-18的产额应>1.7 [mCi/min]（目标5） 可以用两种标记前体合成24个连续单位剂量的[18 F]FLT;（目标6）24个连续单位[18 F]FLT剂量将符合美国和欧盟药典要求。第三阶段的支持将来自ABT目前的投资者，并将使[18 F]FLT的分配，取决于获得NIH快速通道支持和满足第一阶段和第二阶段的研发目标。

 DESCRIPTION (provided by applicant): Worldwide, a person dies from cancer every 5 seconds. Positron emission tomography (PET) is an effective tool that is critical in diagnosing cancer and monitoring treatment efficacy. PET imaging relies on use of short-lived radioisotopes. Commercial distribution of the most commonly used radio tracer, [18F]FDG, has resulted in 80% patient population coverage in the U.S, Western Europe and Japan. However, the "emerging world" (~85% of the world's population) still does not have ready access to [18F]FDG. ABT Molecular Imaging, Inc. (ABT) is focused on increasing PET access in the U.S. and worldwide. The firm's proprietary "Dose on Demand(tm)" Biomarker Generator (BG) greatly simplifies production of [18F]FDG. It also reduces the investment required by healthcare institutions to introduce PET diagnostics into new regions. The need for PET- related advances remains, however. The [18F]FDG biomarker is not the only one required for successful diagnosis/treatment monitoring of cancers. [18F]FLT has been shown to provide complementary information [18F]FDG regarding tumor proliferation in a range of cancers constituting 72% of all existing cases (see Comm. Plan Section A), yet it costs $3000-$4000/dose where available. [18F]FLT has shown so much promise that the National Cancer Institute has an established IND (11/2004) for [18F]FLT to actively encourage investigators to cross-file on (there are more than 350 clinical trials). The Fast Track SBIR project proposed here will provide the funding needed to develop and validate ABT's ability to automatically synthesize and perform automatic QC testing on [18F]FLT simplifying site IND submissions with ABT support. The envisioned ABT system will generate [18F]FLT for ~$250/dose using disposable dose-synthesis cards that can be used in-between [18F]FDG doses. The challenges to integrating [18F]FLT are (1) producing enough F-18 to account for the synthesis yield of [18F]FLT, (2) automating synthesis, and (3) automating QC tests of [18F]FLT on the BG system. For this Fast Track, ABT's PI, Dr. Khachaturian, will lead an expert R&D team of 12 in pursuing 3 Phase I and 3 Phase II Aims: (Aim 1) Validate the feasibility of increasing the amount of [18F] produced by the cyclotron from 1 to 1.7 [mCi/min]; (Aim 2) produce one unit dose of [18F]FLT (2.0-3.6 [mL], 2.5-5 [mCi]) with both US and EU precursors; and (Aim 3) pass the US and EU pharmacopeia quality controls tests. Phase I verification will fully validate proof of concept, such that Phase II development ca focus on ensuring consistent [18F]FLT yield and quality for manufacturing. The Phase II Aims are: (Aim 4) F-18 yield shall be >1.7 [mCi/min] at 3s for n = 4 targets and 20 runs/target; (Aim 5) 24 consecutive unit doses of [18F]FLT can be synthesized with both labeling precursors; and (Aim 6) 24 consecutive unit [18F]FLT doses will pass the US and EU pharmacopeia requirements. Phase III support will come from ABT's current investors and will enable the distribution of [18F]FLT, contingent upon receiving the NIH Fast Track support and meeting the Phase I and II R&D goals.