Chemistry Core

这是对拟议的ICMIC专业 资源B，化学核心。申请人感谢审查小组的许多积极评价 和建设性的反馈意见。很明显，评论家们赞赏 核心和配套人才和资源的优势，致力于发展和 为ICMIC的计划提供光学和MR代理。然而，评论家们也有一些 委员会对核心小组的组织表示关切，并认为有些方面没有得到明确说明。在这次修订中， 我们已经解决了上次审查中的所有主要和次要问题， 关于我们提议的核心的能力和结构的大量新的相关信息。核心 人员与上次提交的报告相比保持不变，在过去的一年里，他们共同努力， 委托新的化学实验室，这将是拟议的核心的核心。下面，我们将讨论 详细说明审查中提出的最重要问题，并总结我们的答复。 “不幸的是，这篇核心文章的重点是与四项研究有关的设备和初步工作。 项目，而不是更全面地了解能力。几乎没有讨论费用 结构和商业模式。" 修改后的核心描述已更改，以提供更多关于我们能力的概述， 其中一些最好通过仔细审查与具体项目有关的最近成就来说明。我们 现在还包括一个更完整的财务计划，我们已经澄清了与调查相关的费用 生产一般而言，核心小组的优先事项将由核心小组工作人员在行政部门的指导下确定 指导委员会。各个项目的需求不同。我们试图区分 提供已经发展到一定成熟阶段的探测器（并且可以 以名义成本“按需”提供），以及那些涉及更多创新和探索性化学的 (and这需要更多的原创性研究和开发）。核心的供应预算已 增加了这些费用，以更充分地支付这些需要。我们希望修改后的报告充分描述了 我们的整体能力，此外还显示了如何促进个别项目。 “化学核心集中在新的光学试剂的开发。一些光学代理 已经可以通过该核心常规获得，并且新药剂的合成也出现在 目前的工作范围。虽然MR试剂在研究项目4中描述，但它们的合成是。不 在核心中充分描述” 我们在化学核心的背景下排除了对MR探头能力的描述， 上一次提交中的疏忽。此外，当时我们设想获得新的蛋白水解MR 第四，从工业来源。我们现在在第[6]节中包括DOTA-肽的合成 探针和对MMPs作用敏感的MR试剂的开发。值得注意的是，我们的化学 团队在MR分子成像剂的设计、合成和修饰方面具有丰富的经验。博士 Don Molting已经接受了设计金属螯合物作为MR造影剂的正式培训，而Pham博士， Bornhop和Manning在这一领域有许多出版物（见研究者简介）。此外，博士。 Pham在磁共振造影剂氧化铁的设计和开发方面做了大量工作。核心 优先次序将根据项目的需要确定，总体而言， 而不是新的磁共振剂。 “核心预算中的一个问题是，曼宁博士也在研究项目1上，范博士在研究项目1上。 研究项目4.目前还不清楚他们的时间将如何分配和计费。'" 在化学核心和研究项目1和4中的努力分配并没有反映出 曼宁博士和范博士的工作是重复的在项目1和4中，他们的工作将集中在 特别是创新的发展和探索性的化学是具体到这些项目。他们的 对这些项目的努力分配反映了他们对这些项目的原始智力思想的投资。 然而，除此之外，他们每个人都将承担更一般的责任，以满足其他项目的需要 以及通过核心提供已经发展到更成熟阶段的代理。我们本可以选择 他们把所有的精力都放在核心上，但觉得把一些时间分配给特定的项目更合适， 他们与这些研究项目的密切联系。总的来说，我们认为他们的努力是合理的， 提出的工作范围。 “一个缺点是，它是有点虚伪，目前的工作中所描述的第B节（设计 一种NIR受体猝灭剂）作为新的和探索性的，因为它具有 在2002年，核心主任和他的顾问已经发表了，当时他是一名博士后研究员， 博士他在哈佛医学院。'" 在我们上次提交的材料中，我们没有充分说明， NIRQ 750的修改是对核心主任 在过去开发的（Pham等人Angew. Chem.Int.Ed.2002，41，3659-62）。我们同意，总体而言， 在技术上并不新颖，我们现在已经将这种代理作为一种已建立的探针。

INTRODUCTION TO THE REVISED PROPOSAL This is a first revision of the proposed ICMIC Specialized Resource B, the Chemistry Core. The applicants thank the review panel for their numerous positive comments and constructive feedback regarding the previous submission. Clearly the reviewers appreciated the value of the Core and the advantages of supporting personnel and resources dedicated to the development and provision of optical and MR agents for the programs of the ICMIC. However, the reviewers also had some concerns about the organization of the Core and felt some aspects were not clearly described. In this revision, we have addressed all of the major and minor concerns from the previous review and have added a substantial quantity of new, relevant information regarding the capability and structure of our proposed Core. The Core personnel remain unchanged from the previous submission, and in the past year they have worked together to commission new chemistry laboratories that would be the heart of the proposed Core. Below, we discuss in detail the most significant concerns raised in the review and summarize our response. "Unfortunately, this Core write up focuses on equipment and preliminary work linked to the four Research Projects, rather than a more comprehensive glimpse at capabilities. There is little to no discussion of fee structure and business model." The revised Core description has been changed to provide more of an overview of our capabilities, and some of these are best illustrated by closely examining recent achievements relevant to specific projects. We also now include a more complete financial plan and we have clarified the costs associated with probe production. In general the priorities of the Core will be set by the Core staff with guidance from the Executive Steering Committee. The individual projects differ in their needs. We have attempted to distinguish between the provision of probes that have already been developed to a stage of some maturity (and which can be provided "on demand" for nominal costs), and those that involve more innovation and exploratory chemistry (and which require more original research and development). The supply budget of the Core has been increased to more fully cover the costs of these needs. We hope the revised write-up adequately describes our overall capability, and in addition shows how the individual projects will be facilitated. "The Chemistry Core concentrates on the development of new optical agents. A number of optical agents are already routinely available through this Core and the synthesis of newer agents appears well within the scope of the present work. While MR agents are described in Research Project 4, their synthesis is. not adequately described in the Core" Our exclusion of a description of the MR probe capability within the context of the Chemistry Core was an oversight in the previous submission. In addition, at that time we envisioned obtaining the novel proteolytic MR agent of Project 4 from an industrial source. We now include in section [6] the synthesis of DOTA-peptide probes and the development of MR agents sensitive to the effects of MMPs. It is noteworthy that our chemistry team has extensive experience on the design, synthesis and modification of MR molecular imaging agents. Dr. Don Molting has been formally trained in the design of metal chelates as MR contrast agents, while Drs Pham, Bornhop, and Manning have many publications in this area (see investigator bio-sketches). In addition, Dr. Pham has worked extensively on the design and development of iron oxide agents for MR contrast. The Core priorities will be determined by the needs of the projects and overall there is a greater emphasis on new optical and nuclear agents than on new MR agents. "One issue in the Core budget is that Dr. Manning is also on Research Project 1 and Dr. Pham is on Research Project 4. It is not clear how their time will be divided and billed.'" The apportionment of effort in both the Chemistry Core and Research Projects 1 and 4 does not reflect duplication of effort on the part of Drs. Manning and Pham. Within Projects 1 and 4 their efforts will be focused on particular innovative developments and exploratory chemistry that are specific to those projects. Their allocation of effort to those projects reflects their investment in the original intellectual ideas of those programs. In addition, however, they each will have more general responsibility for meeting the needs of other projects and for providing, via the Core, agents that have advanced to a more mature stage. We could have elected to put all their efforts into the Core but feel allocating some of their time to specific projects more properly reflects their close involvement with those research programs. Overall, we feel their total effort is reasonable given the scope of work proposed. "One weakness is that it is somewhat disingenuous to present the work described in Section b (Design of a NIR acceptor quencher) of "Proposed Novel Synthetic Chemistry" as new and exploratory since it had already been published in 2002 by the Core Director and his advisors while he was a postdoctoral fellow with Dr. Tung at Harvard Medical School.'" In our last submission, we did not adequately communicate that the synthetic work regarding the modification of NIRQ750 was a technical amendment to an established method that the Core Director developed in the past (Pham et al. Angew. Chem. Int. Ed. 2002, 41, 3659-62). We agree that overall this work is not technically novel, and we have now included this agent as an established probe that will be available.