This report is concerned with an efficient, Cu(I)-mediated method for the radiosynthesis of [(18)F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Three (18)F-labelled radiotracer candidates were synthesised from [(18)F]fluoride ions as proof of principle. The new protocol is widely applicable for the synthesis of novel radiotracers in high radiochemical yields.
Positron emission tomography (PET) imaging of misfolded protein aggregates
that form in neurodegenerative
processes of the brain is key to providing a robust marker for improved
diagnosis and evaluation of treatments. We report the development
of advanced radiotracer candidates based on the sulfoxide scaffold
found in proton pump inhibitors (lansoprazole, prevacid) with inherent
affinity to neurofibrillary tangles in Alzheimer’s disease
and related disorders (e.g., dementia with Lewy bodies and the frontotemporal
degeneration syndrome). First-in-man results obtained with [18F]lansoprazole and N-methyl-[18F]lansoprazole
were used to guide the design of a set of 24 novel molecules with
suitable properties for neuroimaging with PET. Compounds were synthesized
and characterized pharmacologically, and the binding affinity of the
compounds to synthetic human tau-441 fibrils was determined. Selectivity
of binding was assessed using α-synuclein and β-amyloid
fibrils to address the key misfolded proteins of relevance in dementia.
To complete the pharmacokinetic profiling in vitro, plasma protein
binding and lipophilicity were investigated. Highly potent and selective
new radiotracer candidates were identified for further study.
Imaging of the mu opioid receptor (MOR) availability with positron emission tomography (PET) is a pertinent challenge in Neuroscience. Both, regulation of receptor expression and occupancy by endogeneous opioids play into cognitive and behavioral phenotypes of healthy function and disease. Receptor expression in the active and inactive states can be measured using high affinity radioagonist and radioantagonist PET tracers, respectively. Occupancy assessment requires radioligands showing competitive and reversible binding with moderate affinity to the MOR, which may lead to physical extinction of the receptor specific signal in vivo. We investigated a moderately potent, selective MOR agonist in rat to test if a radiotracer design paradigm tailored to competition with endogeneous opioids leads to viable imaging results. The benzamide 3,4-dichlorobenzenecarboxylic acid (dimethylamino)cyclohexyl)methyl amide (AH-7921, 1) was synthesized and characterized in rat brain using autoradiography and positron emission tomography. Compound 1 was found to activate with low nanomolar potency the MOR and to a lesser extent KOR as a full agonist. Concentration dependent binding studies with agonist and antagonist radioligands were conducted to assess competition behavior and obtain inhibition constants. Kinetic analysis of 3,4-dichlorobenzene[C]carboxylic acid (dimethylamino)cyclohexyl)methyl amide binding in rat brain resulted in low but reproducible binding potential in the thalamus (0.8 ± 0.1). A radioactive metabolite was detected in brain (17%, after 15 min). Nonetheless, we conclude that quantitative imaging of MOR availability is possible when using a moderate affinity radiotracer.
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