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.
Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-inman imaging studies with the potential novel tau imaging agent [ 18 F]N-methyl lansoprazole ([ 18 F]NML). Herein we report validation of the synthesis of [ 18 F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether *
We developed a versatile, rapid, and robust high‐yielding radiochemistry‐adapted protocol utilizing formamides as masking groups for secondary and tertiary amines. Selective reducing conditions were devised using borane reagents. In this protocol formamide functionalities were found to have an orthogonal reactivity to most other carbonyl functions, while effectively protecting amines from oxidative degradation. We exemplify the newly developed methodology by synthesizing a µ‐opioid PET radiotracer and a phenethylamine PET radiotracer analogue.
The
3,4-dichloro-
N
-(1-(dimethylamino)cyclohexyl)methyl
benzamide scaffold was studied as a template for
18
F-positron
emission tomography (
18
F-PET) radiotracer development emphasizing
sensitivity to changes in opioid receptor (OR) occupancy over high
affinity. Agonist potency, binding affinity, and relevant pharmacological
parameters of 15 candidates were investigated. Two promising compounds
3b
and
3e
with μ-OR (MOR) selective agonist
activity in the moderate range (EC
50
= 1–100 nM)
were subjected to
18
F-fluorination, autoradiography, and
small-animal PET imaging. Radioligands [
18
F]
3b
and [
18
F]
3e
were obtained in activity yields
of 21 ± 5 and 23 ± 4% and molar activities of 25–40
and 200–300 GBq/μmol, respectively. Displaceable binding
matching MOR distribution in the brain was confirmed by imaging. Radioligands
showed a rapid pharmacokinetic profile; however, metabolite-corrected,
blood-based modeling was required for data analysis. Observed BP
ND
was low, although treatment with naloxone leads to a marked
decrease in specific binding, confirming the discovery of a new template
for
18
F-labeled OR-agonist PET ligands.
We report the synthesis, radiosynthesis and biological characterisation of two gonadotropin‐releasing hormone receptor (GnRH−R) antagonists with nanomolar binding affinity. A small library of GnRH−R antagonists was synthesised in 20–67 % overall yield with the aim of identifying a high‐affinity antagonist capable of crossing the blood–brain barrier. Binding affinity to rat GnRH−R was determined by autoradiography in competitive‐binding studies against [125I]buserelin, and inhibition constants were calculated by using the Cheng–Prusoff equation. The radioligands were obtained in 46–79 % radiochemical yield and >95 % purity and with a molar activity of 19–38 MBq/nmol by direct nucleophilic radiofluorination. Positron emission tomography imaging in rat under baseline conditions in comparison to pretreatment with a receptor‐saturating dose of GnRH antagonist revealed saturable uptake (0.1 %ID/mL) into the brain.
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