Chemistry Core

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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.