FABP3 TARGETED RADIOLIGANDS
Fatty acid binding protein 3 transports polyunsaturated fatty acids within the brain and is also a putative α-synuclein chaperone protein. We are interested in FABP3 as a target due to human and animal data showing co-expression with α-synuclein aggregates. These aggregates for Lewy bodies which are pathological hallmarks of Parkinson's disease or Dementia with Lewy Bodies (DLB). Genetic knock-out and pharmacological blockade of FABP3 has been shown to ameliorate motor and cognitive deficits in Lewy body animal models. This project involves library synthesis, radiolabeling, in vitro and in vivo evaluation. By developing an effective FABP3 radioligand, we hope to elucidate the role of FABP3 in neurodegenerative diseases in living brains.
The ubiquitous presence of carbon in small molecule exogenous compounds makes it attractive for isotopic labeling. Carbon-11 radiochemistry, despite its relatively short half-life, offers numerous opportunities for tagging molecules with a positron emitter. Nucleophilic [11C]methylations with [11C]CH3I or [11C]CH3OTf have long been used to generate some of the most prominent radiotracers. To expand this field, we seek to build upon a strong foundation of [11C]CO2 radiochemistry and advance mild reduction chemistries. These will permit robust amide reductions to access heteroatom-alkyl chains longer than methyl and for direct methylation of amines through fixation-reduction mechanisms. Moreover, we are seeking to improve the production and expand the reaction scope of underutilized synthons (CH3NO2, CH2O, CHF3, or CF2O).
IMPROVED ACCESS TO NEUROIMAGING
High infrastructure costs limits PET to large population areas; thus, patients not located near major research centres may have trouble accessing these tests or cannot readily be recruited into large research studies (i.e. ADNI). With new dementia diagnoses expected to rise most quickly in low- and middle-income countries, where PET infrastructure is limited, a large and important cohort will be excluded from these seminal studies and creates health care disparity. Locally, we are investigating barriers to accessing PET technology by rural residents of Canada. To truly evaluate, a direct comparison between SPECT alternatives to gold standard PET probes is needed, however, the former do not exist. Some promising examples were recently reported but have yet to be replicated. Our short-term contribution to this area is to replicate these studies and further evaluate candidate SPECT radiotracers in animal models. Long term, SPECT alternatives for as many protein targets as possible will be generated to minimize barriers to accessing nuclear molecular neuroimaging.
PRECLINICAL RADIOTRACER SUPPLY
Supporting local imaging collaborators is a key role for our team. Beyond de novo radiotracer discovery, there are plenty of excellent PET radiotracers reported in the literature which we can quickly bring online in locally. While using an off-the-shelf procedure simplifies the process, we are not a group that rests on our laurels. Improving the efficiency and reliability of radiotracer supply is an active area of research, particularly for undergraduate projects. As a few examples, we have 1) developed a solid-supported production of TFB for reporter gene imaging, 2) automated Al-F labeling of FAPI-74, and 3) conducted a flow radiolabeling of 11C-butanol.
AUTOMATION AND RADIOPHARMACUETICAL TRANSLATION
As part of an interdisciplinary team of molecular imaging scientists and clinicians, we are often tasked with translating radiopharmaceuticals from other sites. Either for preclinical or clinical applications, these new-to-us radiopharmaceuticals require optimization for our equipment and site set up. To meet the ever growing library (and regulatory) demands, we are constantly exploring was to improve radiolabeling efficacy and robustness. To date, these efforts have focused upon very short half-life products such as O-15 water and N-13 ammonia. We have built an automated purification system and adapted commercial quality testing equipment to streamline production processes and make them more reliable. Readily available microprocessing boards, such as Arduino and Raspberry Pi, and on-site 3D printing makes for practical, low-cost, and near limitless laboratory optimization.
Lawson Health Research Institute Internal Research Fund
Saint Joseph's Health Care London Foundation; Fiona Monckton Fund
Canadian Institute for Health Research
New Frontier in Research Fund - Exploration
BrainsCAN (Canada First Research Excellence Fund)
Canadian Foundation for Innovation
Schulich School of Medicine and Dentistry, Western University Collaborative Research Grant
Academic Medical Organizations of Southern Ontario
Joint Programme - Neurodegenerative Disease Research
Alzheimer's Society of Canada