18F-labeled Alpha-Synuclein Ligands for PET Imaging of Lewy Bodies
Critical Challenges in PD: Alpha-synuclein Neuroimaging, 2009
The Avid-ProteoTech program aims at identifying radiopharmaceuticals for PET imaging of Lewy bodies in the human brain. Lewy bodies, formed by aggregates of alpha-synuclein, are a defining pathological feature in the brain of Parkinson patients. At the current time, the Lewy bodies can only be assessed following autopsy. Visualization of Lewy bodies in living patients by PET imaging is expected to help in the diagnosis and prognosis of Parkinson’s disease as well as to facilitate clinical trials with disease-modifying drugs.
ProteoTech Inc. has discovered small organic molecules, which prevent and/or disrupt aggregation of alpha-synuclein aggregates in cell culture and animal models of Parkinson’s disease. One of these molecules is currently being studied in a Phase I clinical trial for Alzheimer’s disease. Avid Radiopharmaceuticals Inc. has expertise on converting bioactive molecules to 18F-labeled compounds suitable for 18F-labeled PET imaging and is currently developing flurpiramine F18 a selective imaging agent for beta-amyloid protein (Ab) aggregates for Alzheimer’s disease, in Phase II and Phase III clinical studies. ProteoTech Inc. and Avid plan to collaborate on the discovery and development of 18F-labeled PET imaging agents for alpha-synuclein aggregates in Lewy bodies. This collaboration brings together two teams with unique and complementary expertise.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Lewy bodies are known to play a crucial role in the disease process of Parkinsonism. Visualizing them in living patients will make it possible to better define their role, and to test whether they are deposited before the onset of clinical manifestations of the disease. Imaging Lewy bodies in patients will thus help in the early identification of Parkinsonism, in the differential diagnosis of various forms of Parkinson’s disease as well as dementias, and in the prognosis for patients. In addition, since many emerging disease-modifying therapies for Parkinson’s disease target the alpha-synuclein aggregates in the Lewy bodies, PET imaging methods will provide a biomarker for such clinical trials.
The Avid-ProteoTech program is expected to identify radiopharmaceuticals for PET imaging of Lewy bodies, suitable for formal development to FDA approval
INTERIM PROGRESS REPORT
The project aims to identify radioactive, 18F-labeled new chemical entities that bind with high affinity and selectivity to alpha-synuclein aggregates and have adequate pharmacokinetic properties and brain penetration to be suitable as PET radiopharmaceuticals. Based on inhibitors of alpha-synuclein aggregation earlier discovered at ProteoTech, a new chemical series has been established and is currently being expanded. New chemical entities are optimized for selective and potent binding to alpha-synuclein aggregates and suitability for radioactive modifications. The project currently is in its productive chemical synthesis phase. Initial understanding of the structural activity relationship (SAR) for alpha-synuclein aggregate ligands has been obtained. Data obtained so far are supportive of the view that compounds with adequate binding affinity and selectivity suitability for radioactive substitutions can be generated.
The project aims at identifying radioactive, 18F-labeled new chemical entities that bind with high affinity and selectivity to alpha-synuclein aggregates and has adequate pharmacokinetic properties and brain penetration to be suitable as PET radiopharmaceuticals. Based on inhibitors of alpha-synuclein aggregation earlier discovered at ProteoTech, a new chemical series has been established and expanded. The goals have been partially achieved. The best compounds so far bind with low nanomolar affinity (Ki = 30nM) to alpha-synuclein aggregates and show modest brain penetration. Both affinity and brain penetration are being optimized to obtain suitable PET ligands, With continued efforts, these goals are likely attainable.
Publication Based on MJFF Funding:
No abstracts or publications have generated as yet with the existing data.
A brief summary of the project was presented at a recent scientific conference: Harvard NeuroDiscovery Center Annual Symposium: Progress in Molecular Neurology: A Parkinson’s Disease Perspective. F. Hefti: “PET Radiopharmaceuticals for Detection and Differential Diagnosis of Parkinson’s Disease”. November 16, 2009. Harvard Medical School, Boston, Massachusettts.
Grants Made Possible with MJFF Funding:
No additional direct funds have been sought for this project.
The project received indirect institutional support from Avid Radiopharmaceuticals and ProteoTech Inc., in the form of time of support staff, costs of general supplies, and access to equipment.
President and Chief Operations Officer at NeuroPhage Pharmaceuticals
Location: Cambridge, Massachusetts, United States
Chairman, President and Chief Scientific Officer at ProteoTech Inc.