This Program Announcement expires on December 7, 2004, unless reissued. DEVELOPMENT OF PET AND SPECT LIGANDS FOR BRAIN IMAGING (SBIR AWARD) Release Date: December 4, 2001 PA NUMBER: PA-02-028 (This PA has been reissued, see PA-05-122) National Institute of Mental Health (http://www.nimh.nih.gov/) National Institute of Deafness and Other Communication Disorders (http://www.nidcd.nih.gov/) National Institute of Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov/) National Institute on Drug Abuse (http://www.nida.nih.gov/) National Institute on Aging (http://www.nia.nih.gov/) National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov/) National Institute of Environmental Health Sciences (http://www.niehs.nih.gov/) PURPOSE The use of radiotracers for imaging molecular events in preclinical and clinical studies is essential for understanding the biological basis of normal brain function and the pathophysiology of brain disorders. Nevertheless, there is a paucity of versatile agonist and antagonist positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers for molecular targets that are implicated in brain disorders. The intent of this Program Announcement (PA) is to invite applications for the commercial development of novel radioligands for PET and SPECT imaging in human brain, and to incorporate pilot or clinical feasibility evaluation in pre-clinical studies, model development, or clinical studies. Specifically, this Program Announcement (PA) solicits Small Business Innovation Research (SBIR) grant applications proposing the development of PET and SPECT probes for molecular targets (e.g., receptors, intracellular messengers, disease-related proteins) that are of broad interest to the neuroscience research community. These radiotracers will be used for neuroimaging as well as potential biological markers and surrogate endpoints for translational and clinical research, drug discovery and development, and clinical trials. Also appropriate for this PA are applications proposing research and development of new technologies for radiotracer development. This PA must be read in conjunction with the Omnibus Solicitation of the NIH, CDC and FDA SBIR and STTR Grant Applications found at http://grants.nih.gov/grants/funding/sbir.htm, the instructions for Phase II Grant Applications found at http://grants.nih.gov/grants/funding/sbir2/index.htm, and the PHS 398, instructions (http://grants.nih.gov/grants/funding/phs398/phs398.html). Except as noted below, all instructions and information in these documents also apply to applications submitted in response to this PA. This PA inviting SBIR applications is a parallel solicitation to RFA-MH-02-003, (Development Of PET and SPECT Ligands for Brain Imaging (Phased Innovation Award), which is a request for R21 and R33 applications with a single application receipt date (see http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-02-003.html). HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This PA, Development of PET And SPECT Ligands for Brain Imaging (SBIR Award), is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Eligibility requirements for Phase I and Phase II grants are found at http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf and http://grants.nih.gov/grants/funding/sbir2/index.htm, respectively. MECHANISM OF SUPPORT-PHASE I Phase I applications in response to this PA will be funded as Phase I SBIR Grants (R43) with modifications as described below. Responsibility for the planning, direction, and execution of the proposed research will be solely that of the applicant. Applications for Phase I grants should be prepared following the instructions at http://grants.nih.gov/grants/funding/phs398/phs398.html. o Project Period and Amount of Award Because the length of time and cost of research involving complex radiotracer development and development of associated technologies often exceed those routinely awarded for SBIR grants, a project period up to two years and a budget not to exceed a total cost of $250,000 per year (direct costs, indirect costs and fixed fee) will be considered under this PA if the time period and amount are well justified. See section, BUDGET REQUESTS GREATER THAN $100,000 TOTAL COSTS, in http://grants.nih.gov/grants/funding/phs398/phs398.html for instructions on submitting a budget greater than $100,000. o Consultant and contractual costs. The total amount of all consultant costs and contractual costs normally may not exceed 33% of the total costs requested for Phase I SBIR applications. However, Phase I grant applications submitted under this PA may exceed this limit when well justified and when those costs are necessary to support clinical studies or trials. MECHANISM OF SUPPORT - PHASE II Phase II applications in response to this PA will be awarded as Phase II SBIR grants (R44) with modifications as described below. Phase II applications in response to this PA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The previously funded Phase I award need not have been submitted in response to this PA, but the Phase II proposal must be a logical extension of the Phase I research. Phase II applications should be prepared using instructions at http://grants.nih.gov/grants/funding/phs398/phs398.html. o Project Period and Amount of Award Because the length of time and cost of research involving complex radiotracer development and development of associated technologies often exceed those routinely awarded for SBIR grants, a project period up to three years and a budget not to exceed total costs of $450,000 per year (direct costs, indirect costs and fixed fee) will be considered under this PA if the time period and amount are well justified. o Consultant and contractual costs The total amount of all consultant costs and contractual costs normally may not exceed 50% of the total costs requested for Phase II SBIR applications. However, Phase II grant applications submitted under this PA may exceed this limit when well justified and when those costs are necessary to support clinical studies or trials. MECHANISM OF SUPPORT-FAST TRACK Applications for Fast Track SBIR grants should be prepared following the instructions for Phase I and Phase II applications at http://grants.nih.gov/grants/funding/phs398/phs398.html, and the additional instructions at http://grants.nih.gov/grants/funding/sbirsttr1/sbirsttrft-rs.pdf. The total duration of Phase I and Phase II cannot exceed 5 years for fast track applications, and the budget levels described above for Phase I and Phase II applications apply. RESEARCH OBJECTIVES Tremendous opportunities exist for the application of PET and SPECT imaging in studies of the pathophysiology and treatment of brain disorders, but relatively few radioligands are currently available for functional imaging of target molecules implicated in normal brain function and in brain and behavioral disorders. A recent workshop, "Consortium for the Development of Novel PET and SPECT Ligands for Brain Imaging", organized by the National Institute of Mental Health (NIMH) together with six other National Institutes of Health (NIH) institutes, explored opportunities to work collaboratively across academia, industry, the Food and Drug Administration (FDA), and NIH institutes to accelerate radiotracer development. The participants proposed several ways in which NIMH could foster radioligand development: a) partnering with industry, including possible means to address intellectual property rights issues, b) implementing targeted research initiatives specifically for the development of radioligands, and c) establishing an annual meeting of a consortium (industry, academia, NIH, and the FDA) to continue exploring ways to stimulate radioligand development. A detailed summary of the workshop is available at http://www.nimh.nih.gov/research/imagingsummary.cfm. The need for NIH to encourage effective partnering with industry on radioligand development was also stressed by participants at an NIH-supported forum entitled "PET Tracers as Intellectual Property" held at the October 2000 meeting of the Society for Non-Invasive Imaging in Drug Development. This initiative is intended to stimulate the development of radioligands for molecular targets (e.g., receptors, cell adhesion molecules, intracellular messengers, and disease related proteins) that are of broad interest to the scientific community. The widespread availability and use of these radioligands are expected to: 1) accelerate research on identifying and characterizing the neural circuits and pathways implicated in the pathophysiology of brain disorders, and 2) facilitate the identification of new therapeutic targets and the development of new compounds as potential therapeutic agents. Exploratory studies on the identification of novel targets or the identification of base compounds for specific molecular targets are not appropriate topics for this initiative. Molecular targets for which radioligands are needed, and for which research and development is solicited under this PA include, but are not limited to, those listed below. Please contact program staff listed under INQUIRIES to determine program priorities and molecular targets of interest to specific NIH institutes or refer to the internet addresses listed above for each of the participating NIH institutes. o Receptors: adenosine, adrenergic: alpha 1, alpha 2, cannabinoid: CB1, CB2, corticotropin releasing hormone: CRH R1, CRH R2, dopamine: D1, D3, D4, D5, & low affinity DA receptors, estrogen, GABA A subunits, GABA ion channel, GABA B, glutaminergic, glycine site, metabotropic glutamate subtypes, muscarinic subunits, neurokinin receptors: NK1, NK2, NK3, nicotinic receptor subunits: alpha 7 & alpha 4 beta 2, NMDA subunits, opioid receptors: mu, delta, kappa, serotonin: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, sigma ligand, substance P, voltage gated ion channels: Ca, Na, K M current proteins o Transporters: vesicular ACh, GABA glutamate, NET, SERT o Enzymes: choline acetyltransferase, dopamine beta-hydroxylase, GABA transaminase, glutamic acid decarboxylase, glutaminergic, phosphodiesterases, tyrosine hydroxylase o Intracellular targets: amyloid deposition, diacylglycerol, gene expression markers, lipid metabolism, neuroinflammatory markers: cytokines, COX inhibitors, synthases, peptidases, phosphatases, phospholipases, protein kinases, stem cells The following objectives would make appropriate topics for proposed Phase I/Phase II projects. This list is not meant to be all-inclusive o Lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physio-chemical properties allowing radiochemical synthesis o Pre-clinical studies, including: initial pharmacology and toxicology to screen out compounds that are unlikely to be promising candidates for PET or SPECT imaging, radiolabeling procedures, in vitro and ex vivo autoradiography, in vivo imaging including micro PET (rodent and/or primate), and studies of pharmacological specificity, biodistribution, and pharmacokinetics o Model development for quantitation, including development and evaluation of pharmacokinetic models and use of animal models of gradient of binding sites/enzymes to assess sensitivity to changes o Determination of toxicology/pathology (FDA approvable) for submission of and Radioactive Drug Research Committee (RDRC) or Investigational New Drug (IND) application o IND application development and submission to the FDA prior to pilot human studies o Pilot human imaging studies with normal controls, pharmacological challenges with analyses of radiometabolites under the auspices of IRB approval (i.e., RDRC or IND development and submission) o Clinical studies in patient/disease population or experimental manipulations INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. APPLICATION PROCEDURES Applicants should follow the instructions for SBIR Phase I, Phase II or fast-track submissions with the modifications as noted in this PA. The original application and five single-sided copies must be mailed to the NIH Center for Scientific Review. For purposes of identification and processing, the title and number of this PA must be shown in the appropriate place on the face page of the SBIR Phase I or Phase II applications. Follow the mailing instructions in the Omnibus Solicitation for Phase I applications. Follow the mailing instructions in the Phase II application package for Phase II applications. Applicants are encouraged to contact the program staff listed under INQUIRIES with any questions regarding their proposed project and the goals of this PA. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria Review criteria are described in Phase I and Phase II SBIR websites listed above. The Phase I application should specify clear, measurable goals (milestones) that should be achieved prior to initiating Phase II. Failure to provide clear, measurable goals may be sufficient reason for the study section to judge the application non-competitive. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Margaret Grabb, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 6001 Executive Boulevard, Room 7201, MSC 9645 Bethesda, MD 20892-9645 Rockville, MD 20852 (for express or courier service) Telephone: (301) 443-3563 FAX: (301) 443-1731 Email: mgrabb@mail.nih.gov Lynn Luethke, Ph.D. Division of Extramural Research National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-C, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3458 FAX: (301) 402-6251 Email: lynn_luethke@nih.gov Antonio Norohna, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6001 Executive Boulevard, Suite 402 Bethesda, MD 20892-7003 Telephone: (301) 443-7722 FAX: (301) 594-0673 Email: anoronha@willco.niaaa.nih.gov Steven Grant, Ph.D. Treatment Research and Development Division National Institute on Drug Abuse 6100 Executive Boulevard, Room 4238 Bethesda, MD 20892-9559 Telephone: (301) 443-4877 FAX: (301) 443-6814 Email: sgrant@nida.nih.gov Neil S. Buckholtz, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: buckholn@nia.nih.gov Thomas Miller, Ph.D. Technology Development National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, MSC 2139 Bethesda, MD 20892 Telephone: (301) 496-1779 FAX: (301) 402-1501 Email: tm208y@nih.gov Jerrold J. Heindel, Ph.D. Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 FedEx: 79 T.W. Alexander Dr, 4401 Research Commons, 3rd Floor Research Triangle Park, NC 27709 Telephone: (919) 541-0781 FAX: (919) 541-5064 Email: heindelj@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathy Hancock Grants Management Branch National Institute of Child Health and Human Development 6001 Executive Boulevard, Room 8A17M Bethesda, MD 20892-7510 Telephone: (301) 496-5482 FAX: (301) 402-0915 Email: hancockk@mail.nih.gov Ms. Sara Stone Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400B, MSC-7180 Bethesda, MD 20892 Telephone: (301) 402-0909 FAX: (301) 402-1758 Email: stones@nidcd.nih.gov Ms. Judy Fox Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6001 Executive Boulevard, Suite 505, MSC-7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2434 Email: jsimons@willco.niaaa.nih.gov Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: gf6s@nih.gov Ms. Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: whippl@nia.nih.gov Ms. Rebecca Claycamp, CRA Deputy Grants Management Officer National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3258 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: rc253d@nih.gov Carolyn B. Winters Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-7823 FAX: (919) 541- 2860 Email: winters@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 (NIMH), 93.847 (NIDCD), 93.273 (NIAAA), 93.279 (NIDA), 93.886 (NIA), 93.853 (NINDS), and 93.855 (NIEHS). Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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