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 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 mental illnesses that may become targets for new drugs or other therapeutic interventions. Such proteins include several neuroreceptors, transporters, and enzymes. They mostly exist at very low levels in human 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. During the report period, we worked on developing PET tracers for several imaging targets. These include the GluN2B sub-site of the NMDA receptor, orexin-1 and orexin-2 receptors, cannabinoid subtype 2 receptors, 1-adrenoceptors, and a range of enzymes (COX-1, COX-2, PDE4B and PDE4D, CSF-1R, RIPK-1, LRRK-2, and HDAC6). In collaboration with Drs. Richmond (NIMH) and Michaelides (NIDA), we also explored the development of PET tracers for advancing chemogenetic technology as a means for interrogating brain function. 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 led to initially promising tracers for imaging the GluN2B binding site on the NMDA receptor. We continued to evaluate these tracers for their imaging efficacies. in particular, we have been investigating the unexpected uptake of these radiotracers in primate cerebellum. Noradrenergic signaling through α1 adrenoceptors (α1 AR) is implicated in post-traumatic stress disorder. In collaboration with Dr. Garth Terry (University of Washington, Seattle), we have been developing a selective tracer for PET imaging of brain α1 AR. Very promising results have been obtained in rodent and monkey with a tracer dubbed [11C]ARMI. It is now planned to advance this tracer to evaluation in human. Orexin type-1 and 2 receptors play roles in the regulation of reward processing, emotion, pain, feeding, addiction, and the sleep–wake cycle, and are potential targets for the treatment of related disorders. In collaboration with Dr. Changning Wang (Harvard Medical School), we produced and evaluated two candidate tracers for PET imaging of brain orexin receptors. We concluded that higher affinity tracers will need to be developed. Two tracers that we had earlier developed for TSPO imaging, C-11PBR28 and C-11ER176, are now applied by many PET imaging centers to investigate neuroinflammation in response to various neurological insults (e.g., stroke, epilepsy, and neurodegeneration). PET-TSPO imaging however provides limited information on the complex processes underlying neuroinflammation and raises few prospects for new drug development. Therefore, we have been developing tracers for protein targets that have potential to illuminate other biochemical aspects of neuroinflammation in vivo, and which might also become new drug targets. The cyclooxygenase (COX) subtype 1 and subtype 2 enzymes. COXs are targets for well-known anti-inflammatory drugs, such as aspirin and ibuprofen. Very useful C-11 labeled tracers have emerged from our research. Two of these, (C-11PS13 for COX-1 and C-11MC1 for COX-2, are efficacious for PET imaging in humans and are now being used for clinical studies. These tracers may prove useful for the development of improved anti-inflammatory drugs. Prof. Neil Vasdev (Toronto University) is now also exploring these tracers for imaging and drug development in oncology. C-11PS13 is gaining interest for application by other PET centers. We are continuing to work towards the development of tracers with higher sensitivity for imaging COX-2 in brain, and also longer-lived (F-18 labeled) tracers for both COX-1 and COX-2. With respect to imaging broader biochemical aspects of neuroinflammation, we have been exploring the development of tracers for mitochondrial colony stimulating factor-1 receptor (CSF1R) and two kinases, receptor interacting protein kinase (RIPK-1) and, in collaboration with Prof. Yu-Shin Ding (New York University), leucine receptor repeat kinase-2 (LRRK-2). We are collaborating with Dr. Jakob Hooker (Harvard University/MGH) on developing tracers for 5-lipoxygenase protein (FLAP). We have also collaborated with Dr. Daniel Guendel (Helmholtz Centrum, Heidelberg) to evaluate a tracer for brain cannabinoid subtype-2 receptors, a potential biomarker of neuroinflammation. Histone deacetylase-6 (HDAC6) is considered to be a promising drug target for the treatment of many psychiatric disorders. We are collaborating with Dr. Alan Kozikowski (BrightMinds) to develop PET radiotracers that are highly selective for HDAC6. Two candidate F-18-labeled tracers have been produced that show sizeable PET signals in vivo, but which suffer from poor brain entry due to the action of efflux transporters at the blood-brain barrier. Further tracer development is proceeding. PET tracers can provide important information on experimental therapeutics for neuropsychiatric disorders, such as ability to enter brain and 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 phosphodiesterase subtypes as potential targets for treating depression and mild cognitive disorder. Tracer development for two phosphodiesterase subtypes has proceeded very successfully, with one F18 tracer for the B subtype now in clinical use and a C11 tracer proving very promising in animals. The latter tracer is being advanced to evaluation in humans. 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 was progressed towards evaluation in human, but suffers from adverse metabolism. Effort to produce an improved tracer continues. We are advancing methodology for improved tracer development. In particular, we have developed new methods for exploiting radioactive fluoroforms to generate new tracer chemotypes. New ways to use cyclotron-produced F-18fluoride ion for radiolabeling are also being developed. These methodological advances are gradually entering into our tracer design and production program. In addition, 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 tracers that have been developed elsewhere for PET studies in animals or humans e.g., C-11rolipram (for PDE4 imaging). Each PET experiment requires a synthesis of the tracer on the same day, and hence tracer production is a regular and demanding activity.