PET Radiopharmaceutical Sciences

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

The Molecular Imaging Branch exploits positron emission tomography (PET) as an imaging technique for investigating neuropsychiatric disorders, such as depression, schizophrenia, and Alzheimer's Disease. Fundamental to this mission is the development of novel radioactive probes (radiotracers) that can be used with PET to measure abnormal changes in critical brain proteins. Of particular interest are proteins, implicated in the progression of neuropsychiatric disorders, that may become targets for new drugs or other therapeutic interventions. Such proteins include neuroreceptors, transporters, and enzymes. They mostly exist at low levels in brain. The development of new radiotracers is the key to exploiting the potential of PET in neuropsychiatric research. However, a successful PET radiotracer must satisfy a wide range of difficult-to-satisfy chemical, biochemical, and pharmacological criteria. Consequently, PET radiotracer 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 applications for PET imaging steadily increases and far exceeds the range of currently available radiotracers. Our laboratory, the PET Radiopharmaceutical Sciences Section, investigates in depth all chemical aspects of PET radiotracer 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 PET radiotracers 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 radiotracers 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 for a carbon-11 labeled radiotracer has been published by us in Nature Protocols. In the period covered by this report, we worked on developing PET radiotracers for several imaging targets. These include TSPO, the GluN2B sub-site of the NMDA receptor, orexin receptors, and certain enzymes (COX-1, COX-2, PDE1, and PDE4 B and D subtypes, CSF-1R, and RIPK-1). In collaboration with Drs. Richmond (NIMH) and Michaelides (NIDA), we also started to explore PET radiotracer development in support of emerging chemogenetic tools and technology for interrogating brain function. One radiotracer 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 because of a genetic difference, 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 genetically-insensitive TSPO radiotracers. One of our newer radiotracers, C-11ER176, can quantify TSPO in all subjects of identified genotype, and turns out to be one of the highest performing TSPO radiotracers. We are now producing C-11ER176 for clinical studies as are some other imaging centers. We are also developing longer-lived and therefore more broadly useful F-18 labeled versions of this radiotracer. Some of these show high promise in rodents and monkeys, and one of these, dubbed F-18S51, is to be advanced to evaluation in healthy human subjects. We have been developing radiotracers 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 radiotracers 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 radiotracers may provide more biochemical specificity for investigation of neuroinflammation. They can also prove useful for the development of improved anti-inflammatory drugs. Furthermore, these radiotracers are being explored by collaborators at the University of Toronto for imaging and drug development application in oncology, with promising findings. We are continuing to work towards the development of radiotracers with higher sensitivity for imaging brain COX-2, and in addition longer-lived (F-18 labeled) radiotracers for both COX-1 and COX-2. For example, PS13 has now been labeled with longer-lived fluorone-18. We have also been developing radiotracers 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 brains 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 radiotracers for imaging the GluN2B binding site on the NMDA receptor. We are continuing to evaluate these radiotracers for their imaging efficacies. PET radiotracers can provide important quantitative 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 radiotracers for this purpose. These radiotracers 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 radiotracers for phosphodiesterase subtypes has shown some promise, with one radiotracer for the B subtype now in clinical use. One radiotracer for the D subtype performed well in non-human primate but less well in human. Alternatives with improved properties are now being developed through our own medicinal chemistry effort, and with Pharma collaboration. We are advancing methodology for improved radiotracer development. Thus, we have recently developed new agents for radiolabeling applications, notably C-11fluoroform, F-18fluoroform, and C-11carbonyl difluoride. These expand chemical space for radiotracer development. Our recent development of new TSPO radiotracers was in fact enabled through such parallel methodological advances based on novel reactions of selenium compounds. New ways to use cyclotron-produced F-18fluoride ion and C-11carbon monoxide are being developed. These methodological advances are gradually entering into our radiotracer production program. The laboratory continues to be active in training new scientists at graduate and 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.