Alzheimer's disease (AD) is a progressive neurodegenerative disorder afflicting 6 million Americans. The clinical dementia of AD is coupled to a distinct pathology, with β-amyloid plaques, neurofibrillary tangles, and synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is detectable in individuals with the prodromal stage of mild cognitive impairment (MCI). Positron Emission Tomography (PET) imaging is increasingly employed in the study of AD. However, until recently there have been no PET radiotracers that can directly image synaptic density in vivo, which would be of high value in AD diagnosis, as well as in monitoring efficacy of treatments. We have developed 11C-UCB-J as a radiotracer for PET imaging and quantification of the synaptic vesicle glycoprotein-2A (SV2A). In studies in healthy human subjects, 11C-UCB-J displayed excellent properties for quantitative PET imaging of SV2A in the human brain. We have also validated SV2A as an in vivo biomarker for synaptic density. Initial imaging results in MCI/AD patients show specific and distinct SV2A reductions, most pronounced (30-40%) in the hippocampus, which is expected and consistent with postmortem studies, where early degeneration of the entorhinal cortical cell projection to hippocampus and hippocampal SV2A reductions have been observed. Thus, based on these data, 11C-UCB-J appears to be an excellent radiotracer for quantitative imaging of SV2A in the human brain and 11C-UCB-J PET can be an extremely useful in vivo biomarker of synaptic loss in AD. Although 11C-UCB-J proves to be an excellent tracer for synaptic density imaging, a significant drawback is the short half-life (t1/2 = 20.4 min) of its 11C-radiolabel, which precludes its central production and distribution to multiple sites for imaging use, and thus limits its wide application in multi-center clinical trials or as diagnostic agent in clinics. For AD in particular, where drug clinical trials at many institutions are ongoing, the need for a longer-lived radiotracer is evident and one labeled with the 18F-radioisotope (t1/2 = 109.8 min) will be appropriate. Analogous to the development of 11C-PIB and its FDA-approved 18F-labeled counterpart 18F- flutemetamol (Vizamyl®) for β-amyloid imaging in AD, in this application we propose to develop18F-SDM-8, the difluorinated analog of UCB-J, for human neuroimaging, and to validate its use as a imaging biomarker of synaptic loss in MCI/AD. The goal is to provide a “neuroimaging biomarker of synaptic density” for use in the study of the AD continuum and potential diagnosis of AD in its earliest, prodromal stage, as well as in the monitoring of disease progression and efficacy of emerging AD therapies. In addition to AD, the availability of 18F-SDM-8 PET as a general imaging biomarker of synaptic density will enable the investigation of a wide range of neuropsychiatric diseases where abnormalities in synaptic density/plasticity are implicated.

In this application we propose to validate a positron emission tomography (PET) imaging agent as biomarker for synaptic density. As many brain disorders are thought of as “synaptic diseases”, the use of PET imaging to detect synaptic density and its changes in diseases will provide a potentially paradigm-shifting tool to investigate and diagnose Alzheimer's disease and other neurologic disorders, and monitor treatment outcomes.