NIH funding opportunity – Development and Application of PET and SPECT Imaging Ligands as Biomarkers for Drug Discovery and for Pathophysiological Studies of CNS Disorders (R01)

May 23, 2016 by School of Medicine Webmaster

This FOA 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 (especially mental and behavioral disorders, substance abuse, neurodegenerative disorders, and pediatric brain disorders) and brain changes with age, and 2) facilitate the identification of new therapeutic targets and the development of new compounds as potential therapeutic agents.  Research partnerships among investigators in both academia and pharmaceutical and biotechnology industries are encouraged to more rapidly develop PET and SPECT radiotracers and apply neuroimaging in drug discovery, biomarker development/qualification, and pathophysiological studies.

The proposed development of a radioligand (agonist, antagonist, or allosteric modulator) for a molecular target or for a radioimaging probe to monitor changes in a cellular process should be well-justified and the resulting radiotracer fit for the intended purpose.  There is limited interest, without compelling justification, in another tracer of the same class of targets listed in the CNS Radiotracer Table, or for targets in which a radioligand development effort is underway in the pharmaceutical industry.

The preponderance of tracers for molecular targets developed and utilized to date fall into the pharmacologic class of orthosteric antagonists with the most notable exceptions being ligands for benzodiazepine and opiate receptors (see  Our understanding of the relationship between occupancy and downstream effects of agonists and allosteric modulators is still at an early stage such that ligands that would enable more in depth exploration of such relationships would be of particular interest, especially for those neurotransmitter targets that represent opportunities for novel drug discovery.

In addition to PET tracers for potential therapeutic molecular targets, there is interest in tracers that bind to targets that can be used to monitor changes in cellular processes that are linked to brain plasticity or pathophysiology (e.g., neuroinflammation, neurogenesis, mitochondrial function).  For instance, markers of microglial activation would fall into this class as would any binding site alteration that could be linked to neurodegenerative processes.  Applications  to develop these classes of tracers that are not amenable to validation with existing pharmacologic tool compounds should include description of a feasible validation path (e.g., differences in binding as a function of degree of brain pathology such as is the case for PiB (Pittsburgh compound B) or florbetapir measures of amyloid load in Alzheimer’s Disease).

Prioritization of molecular targets for ligand development is an ongoing exercise and interested parties are encouraged to contact one of the NIH Scientific/Research Contacts to discuss the perceived level of need for a particular PET tracer.

Note:  A feasibility assessment (e.g., density and affinity of the tracer target in brain region(s) of interest in post-mortem human brain) must be conducted, or reference to such information in the published literature, before submission of a tracer discovery project.

The following objectives would make appropriate topics for proposed R01 projects.  This list is not meant to be all-inclusive:

  • Lead compound identification/development and syntheses of chemicals with suitable binding affinity, biodistribution, pharmacokinetics, and physiochemical properties allowing radiochemical synthesis.
  • 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.
  • Determination of toxicology (FDA approved) for submission of an exploratory Investigational New Drug (IND) application or IND application.
  • Exploratory IND or IND application development and submission to the FDA prior to pilot human studies.
  • Pilot human imaging studies with normal controls, pharmacological challenges with analyses of radiometabolites under the auspices of IRB approval (e.g., exploratory IND or IND development and submission)
  • Pilot studies of the PET or SPECT radiotracer in patient/disease populations to assess its utility for research in pathophysiology, drug discovery, or biomarker development.

The development and strengthening of partnerships between scientists from academia and the pharmaceutical industry are highly desirable outcomes of this FOA and are strongly encouraged.  Pharmaceutical scientists are encouraged to actively participate as PDs/PIs or key personnel/collaborators.

Institute Interests

Projects proposing to develop probes where PET or SPECT ligands already exist may be of lower programmatic interest to participating ICs, unless applicants provide a compelling case that there are significant advantages to their approach.

NIMH. NIMH supports neuroscience research to discover the causes of mental illness and to develop more effective and safer treatments.  Specifically the NIMH is interested in the discovery of innovative treatment development targets for mental disorders and for advancing our understanding of the pathological processes contributing to disorders.

NIMH is particularly interested in developing probes that can be used to assess adequacy of target engagement in clinical trials that employ an experimental medicine approach

Further information on NIMH research priorities can be found in the NIMH Strategic Plan, Strategic Research Priorities, and Interventions Workgroup Report.

Applicants are strongly encouraged to discuss applications with NIMH staff listed in Section VII – Agency Contact(s) Scientific/Research Contacts.

NIAAA. NIAAA promotes discovery, synthesis and screening of novel small molecules for innovative priority targets, and supports evaluation of their efficacy in validated preclinical models to assess their therapeutic potential for treating alcohol dependence. The focus of proposed research projects should follow that described above, but should be relevant to the mission of NIAAA.

The identification and pursuit of agents towards novel targets previously un-recognized or understudied for the treatment of alcohol abuse disorders are especially encouraged. In particular, NIAAA encourages applications focusing on agents that alleviate craving and dysphoria during protracted abstinence, and agents effective in patients who have co-morbid psychiatric illnesses (e.g., schizophrenia, bipolar disorder). Applications that essentially propose to further extend established or well-studied strategies and agents are not appropriate for this FOA.

Applicants are strongly encouraged to discuss applications with NIAAA staff listed in Section VII – Agency Contact(s) Scientific/Research Contacts.

NIA. NIA supports research relevant to the process of normal aging and age-related diseases and conditions: including normal cognitive aging, age related cognitive decline, mild cognitive impairment (MCI), Alzheimer’s disease and other dementias of aging, and other age–related changes in the CNS that occur during the human lifespan.  NIA is particularly interested in identifying new therapeutic targets and, novel therapeutic agents. NIA is also interested in identifying protective factors or processes that may contribute to slowing or reversing the progression of age related cognitive decline, mild cognitive impairment (MCI), Alzheimer’s disease and other dementias of aging, as well as other age-related adverse molecular, biochemical, genetic, cellular, or physiological changes that contribute to multiple age-related diseases.

NIBIB. The mission of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) is to improve health by leading the development and accelerating the application of biomedical technologies.  The Institute is committed to integrating engineering with the physical and life sciences to advance basic research and medical care.  One way that this is achieved is through the support of research and development of new biomedical imaging and bioengineering tools and technologies to improve the prevention, detection, treatment, and monitoring of disease.  NIBIB supports research from early stage technology development through first in human demonstrations and early feasibility clinical studies.

NIBIB is interested in early stage probe development including synthesis and characterization of novel probes, novel radiolabeling techniques, and the generation of multi-functional probes for multi-modality imaging. Only applications that include early stages of preclinical discovery will be considered by NIBIB. NIBIB will support small, early stage clinical studies as part of a probe development project, but will not support purely clinical studies of already developed probes, or studies that seek to repurpose existing tracers for new uses. NIBIB strongly urges applicants to speak to  Scientific/Research staff prior to submission of an application.

NIDA. NIDA supports research to elucidate the mechanisms underpinning drug addiction and the treatment of substance use disorders (SUDs). The focus of this announcement is to, in addition to the previously well-known targets, identify novel targets (such as TRP channels, oxytocin, and orexin systems etc), identify and develop novel small molecules with the potential to treat SUDs and pain with minimal side-effects, especially the potential for addiction. NIDA is interested in projects in the early stages of preclinical discovery and development.

Deadlines:  standard dates apply


Filed Under: Funding Opportunities