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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected] 

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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected]

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:  [email protected] 

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:  [email protected]

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:  [email protected]

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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