The goal of the K01 research is to help the applicant to establish an independent and highly- competitive research program in the PET tracer development and neuroimaging for neurologic and psychiatric illnesses, with a major focus of developing an optimal radiopharmaceutical for PET imaging study of fatty acid amide hydrolase (FAAH) in the endocannabinoid (eCB) signaling of drug addiction. FAAH is the enzyme responsible for hydrolysing endocannabinoids such as anandamide. As such it plays a major role in setting the tone of the cannabinoid system in the human brain. Inhibition of FAAH is seen as an attractive pharmaceutical and imaging target. In addition there is substantial evidence that FAAH plays a major role in addiction, and in other psychiatric and neurological illnesses. The ability to measure the levels of FAAH in the living human brain would be extremely useful. Not only could the efficacy of potential FAAH inhibitor drugs be measured directly, but the role of FAAH in certain populations could be compared to normal populations (e.g. drug users compared to non-users), affording insights into the role of this important enzyme in normal and diseased subjects. FAAH could be measured in the human brain by the medical imaging technique, positron emission tomography (PET), which creates images of biochemical processes occurring in vivo. Several radiotracers have been developed for PET imaging of FAAH. To date, only carbon-11 (11C;half-life = 20.4 min) labeled radiotracer, [11C]CURB developed by Dr. Neil Vasdev, has been tested and validated in human trials. Pilot data with [11C]CURB demonstrated both the feasibility, and clinical potential, of imaging FAAH. To overcome the PK-based limitations of [11C]CURB, the first fluorine-18 (18F;half-life = 109.7 min) radiolabeled FAAH inhibitor [18F]DOPP was developed. Preliminary evaluation of [18F]DOPP in nonhuman primates showed that this radiotracer is a promising lead radiotracer worthy of further optimization and evaluation for specific imaging of acute changes in eCB signaling pathways on disease presentation. This proposal involves training a junior faculty member in PET neuroimaging studies from bench to bedside and contributing to the field of radiopharmaceutical sciences;a field suffering from a critical shortage of highly qualified personnel. The applicant will also take advantage of the world-class educational resources, faculty members with successful track-records in scientific research and mentoring, and top-tier research facilities to conduct the proposed research. It is the specific aim of this K01 proposal t design, synthesize, and develop fluorinated FAAH inhibitors with optimized kinetics, radiolabel the most promising lead compounds with 18F and evaluate these compounds in nonhuman primates. We will determine the distribution, specific binding and kinetic model of 18F-labeled FAAH inhibitor that will enable us to study mechanisms for FAAH-linked endocannabinoid regulation of addiction. Relevance: This proposal has the potential to improve public health and help patients suffering from addiction through advancement of PET neuroimaging using 18F-labeled FAAH tracer.
Positron Emission Tomography (PET) is a medical technique that creates images of biochemical processes occurring in vivo, where radioactive molecules are injected and the distributions of those molecules are measured using a PET camera. Data can be acquired in animals, in research subjects and eventually in patient care. As the burden of psychiatric illnesses in the United States and worldwide is high, there is a critical need to develop novel PET radiopharmaceuticals to image illness-related processes in the brain. This work will develop key tools designed to advance the scientific understanding of role of fatty acid amide hydrolase in the cannabinoid system in the nonhuman primate brain, for the potential transition into in vivo imaging of patients with drug addiction and other psychiatric diseases.
|Rotstein, Benjamin H; Wey, Hsiao-Ying; Shoup, Timothy M et al. (2014) PET imaging of fatty acid amide hydrolase with [(18)F]DOPP in nonhuman primates. Mol Pharm 11:3832-8|