The translocator protein (TSPO) is an 18 kDa, five transmembrane domain protein subunit of a multimeric complex primarily located on the outer mitochondrial membrane. Although TSPO expression in the brain is low under normal physiological conditions, overexpression of TSPO is associated with microglial activation and neuroinflammation, and has prompted the investigation of this target as a biomarker for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and stroke.[18F]DPA-714 (1 , Fig. 1) is a clinically important radiotracer for positron emission tomography (PET) imaging of TSPO.1 However, O-dealkylation of [18F]DPA-714 is a significant metabolic route in both baboon and human liver microsomes, which provide a level of complexity in developing methods quantitative image analysis .1In an effort to improve the metabolic profile of [18F]DPA-714 in PET imaging, several metabolically fortified analogs have been designed by increasing steric congestion around the alkyl ether. The synthesis and TSPO binding affinities of DPA-714 analogs featuring an a-methyl (2 ), a-gem-dimethyl (3 ), or a-cyclobutyl (4 ) substituent will be presented, along with the metabolic profiles of their fluorine-18 radioisotopes.

Metabolically fortified DPA-714 analogs for improved PET imaging of translocator protein (TSPO)

248th National Meeting (2014)

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