PET Radiopharmaceutical Sciences

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The Molecular Imaging Branch exploits positron emission tomography (PET) as an imaging technique for investigating mental illnesses, such as depression, schizophrenia, and Alzheimer's Disease. Fundamental to this mission is the development of novel radioactive probes (tracers) that can be used with PET to measure abnormal changes in critical brain proteins. Of particular interest are the proteins implicated in neuropsychiatric disorders that may become targets for new drugs or other therapeutic interventions. Such proteins include many neuroreceptors, transporters, and enzymes. They mostly exist at very low levels in brain. New tracers are key to exploiting the potential of PET in neuropsychiatric research. However, a successful tracer must satisfy a wide range of difficult-to-satisfy chemical, biochemical, and pharmacological criteria. Consequently, tracer development is highly challenging. In fact, our research has some parallels with drug discovery in that it entails high effort and heavy risk but can reap rich biomedical rewards. The number of potentially interesting targets for PET imaging steadily increases and far exceeds the range of currently available tracers. Our laboratory, the PET Radiopharmaceutical Sciences Section, undertakes all chemical aspects of PET tracer discovery. We are equipped for medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These short-lived radioisotopes are available to us daily from the cyclotrons of the neighboring NIH Clinical Center (Chief: Dr. P. Herscovitch). Our Section also interacts seamlessly with our Branch's Section on PET Neuroimaging Sciences (Chief: Dr. R.B. Innis) for early evaluation of candidate tracers in biological models and in animals. Subsequent PET research in humans is also performed with the Imaging Section under Food and Drug Administration oversight through 'exploratory' or 'full' Investigational New Drug Applications. All tracers for PET studies in humans are produced within the NIH Clinical Center's current good manufacturing practice (CGMP) laboratory. A detailed example of this type of production has been published by us in Nature Protocols. In the period covered by this report, we worked on developing PET tracers for several imaging targets. These include TSPO, the GluN2B sub-site of the NMDA receptor, orexin receptors, and certain enzymes (COX-1, COX-2, PDE4B and PDE4D, CSF-1R, and RIPK-1). In collaboration with Drs. Richmond (NIMH) and Michaelides (NIDA), we also started to explore the development of PET tracers that can be useful for advancing chemogenetic technology as a means for interrogating brain function. One tracer that we had earlier developed for TSPO imaging (C-11PBR28) is now being applied by many PET imaging centers to investigate neuroinflammation in response to various neurological insults (e.g., stroke, epilepsy, and neurodegeneration). An early unexpected finding was that humans carry either one or both of two distinct forms of TSPO, which interact differently with C-11PBR28, complicating the analysis of PET studies. Consequently, we sought to develop TSPO radiotracers without this inter-subject sensitivity. One of our newer tracers, C-11ER176, can quantify TSPO in all subject types and turns out to be one of the highest performing TSPO tracers. We are now producing C-11ER176 for clinical studies, as are some other imaging centers. We have been developing longer-lived and therefore potentially more broadly useful F-18 labeled versions of this tracer. One of these, F-18FS51, showed promise in rodents and monkeys and was advanced to evaluation in human. However, this tracer performed much less well in human, exemplifying the difficulty and risk in translating PET tracers from preclincial to clinical application. We have been developing tracers for other targets relevant to the study of neuroinflammation, such as the cyclooxygenase (COX) subtype 1 and subtype 2 enzymes. The COXs are biochemical targets for well-known anti-inflammatory drugs, such as aspirin and ibuprofen. Very promising C-11 labeled tracers have emerged. Two of these (C-11PS13 for COX-1 and C-11MC1 for COX-2) show imaging efficacy in humans and are now entering clinical studies. These tracers may provide more biochemical specificity for investigating neuroinflammation. They can also prove useful for the development of improved anti-inflammatory drugs. Furthermore, these tracers are being explored by collaborators at the University of Toronto for imaging and drug development application in oncology. We are continuing to work towards the development of tracers with higher sensitivity for imaging brain COX-2, and in addition longer-lived (F-18 labeled) tracers for both COX-1 and COX-2. For example, PS13 has now been labeled with longer-lived fluorine-18. We are also exploring the development of tracers for imaging other targets of interest for the study of neuroinflammation, such as mitochondrial colony stimulating factor-1 receptor and the kinase, RIPK-1. NMDA receptors are acted upon by glutamate - one of the most important neurotransmitters for implementing normal brain function. Perturbations in NMDA function are strongly implicated in the pathogenesis of schizophrenia and some other disorders such as depression. Our research has led to initially promising tracers for imaging the GluN2B binding site on the NMDA receptor. We are continuing to evaluate these tracers for their imaging efficacies. PET tracers can provide important information on experimental therapeutics for neuropsychiatric disorders, such as ability to cross the blood-brain-barrier and to engage with a target protein. In collaborations with academia and Pharma, we have been developing several tracers for this purpose. These tracers are targeted at proteins that have not previously been imaged in living human brain and that may have eventual clinical research utility. These proteins include subtypes of phosphodiesterase as potential targets for treating depression and mild cognitive disorder. The development of tracers for phosphodiesterase subtypes has shown some promise, with one tracer for the B subtype now in clinical use. One early tracer for the D subtype performed well in non-human primate but less well in human. Alternative tracers with improved properties have been developed through our own medicinal chemistry effort, radiolabeled, and evaluated in monkey. One of these is being progressed towards evaluation in human. We are advancing methodology for improved tracer development. Thus, we have recently developed new radiolabeling agents s, notably C-11fluoroform, F-18fluoroform, and C-11carbonyl difluoride. These expand chemical space for tracer development. New ways to use cyclotron-produced F-18fluoride ion and C-11carbon monoxide are being developed. These methodological advances are gradually entering into our tracer production program. We have developed sensitive LC-MS/MS methods for investigating the sources of dilution of our tracers with the corresponding non-radioactive tracer, because such dilution can compromise tracer performance. Information from these methods can help to improve tracer quality. The laboratory continues to train new scientists at postdoctoral level for this expanding field. We produce some useful radiotracers that have been developed elsewhere for PET investigations in animal or human subjects, e.g., C-11rolipram (for PDE4 enzyme imaging), C-11UCBJ (for synaptic vesicle 2A receptor imaging) and C-11DCZ (chemogenetic tool imaging). Each PET experiment requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity.