In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain

Dukić-Stefanović, Sladjana; Lai, Thu Hang; Toussaint, Magali; Clauß, Oliver; Jevtić, Ivana; Penjišević, Jelena Z.; Andrić, Deana; Ludwig, Friedrich‐Alexander; Gündel, Daniel; Deuther‐Conrad, Winnie; Kostić‐Rajačić, Sladjana; Brust, Peter; Teodoro, Rodrigo

doi:10.1016/j.bmcl.2021.128254

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…Similar finding of an early increase in [ 11 C]DED binding was reported in Tg-ArcSwe mice compared to wild-type littermates [226]. Several novel MAO-B tracers have been developed including [ 11 C]SMBT-1 [227] based on (S)-[ 18 F]THK5117 structure [228] and [ 18 F]6 [229]. In addition, novel astrocytic tracer [ 11 C]BU99008, which targets imidazoline-2 binding sites (I2BS), has showed specific and high-affinity binding property in post-mortem characterization [230].…”

Section: Discussionsupporting

confidence: 57%

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

Ni¹

2021

Preprint

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Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research, and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models are essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models as well as in patients with Alzheimer’s disease, These tools have facilitated our understanding of disease mechanisms, and provided longitudinal monitoring of treatment effect in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood-brain barrier impairment and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes, and discuss outstanding challenges in disease animal models and future outlook in on-chip characterization of imaging biomarkers towards clinical translation.

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Section: Discussionsupporting

confidence: 57%

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

Ni¹

2021

Preprint

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“…For monitoring of the labeling progress, aliquots were taken every 5 min (total reaction time 20 min) and analysed by radio-TLC. In the first labeling experiments, [ 18 F]tetra- n -butylammonium fluoride ([ 18 F]TBAF, generated from [ 18 F]fluoride and ( n -Bu) 4 NHCO 3 under azeotropic drying) in N,N -dimethylacetamide (DMA)/ tert -butanol ( tert -BuOH) with a precursor-to-copper catalyst ratio of 1:3.5 (entry 1 in Table 1 ) was chosen as these conditions have been shown to be efficient for the labeling of several radiotracers in our lab [ 36 , 37 ]. However, an RCY of only 0.6% could be achieved which prompted us to test n -butanol as probably a more efficient alcohol additive [ 32 ] without achieving an improvement.…”

Section: Resultsmentioning

confidence: 99%

Radiosynthesis and Preclinical Evaluation of an 18F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A)

et al. 2022

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The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cascades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an interesting therapeutic and diagnostic target for neurodegenerative and neuropsychiatric diseases as well as for cancer. Aiming at specific imaging of this enzyme in the brain with positron emission tomography (PET), a new triazolopyridopyrazine-based derivative (11) was identified as a potent PDE2A inhibitor (IC50, PDE2A = 1.99 nM; IC50, PDE10A ~2000 nM) and has been radiofluorinated for biological evaluation. In vitro autoradiographic studies revealed that [18F]11 binds with high affinity and excellent specificity towards PDE2A in the rat brain. For the PDE2A-rich region nucleus caudate and putamen an apparent KD value of 0.24 nM and an apparent Bmax value of 16 pmol/mg protein were estimated. In vivo PET-MR studies in rats showed a moderate brain uptake of [18F]11 with a highest standardized uptake value (SUV) of 0.97. However, no considerable enrichment in PDE2A-specific regions in comparison to a reference region was detectable (SUVcaudate putamen = 0.51 vs. SUVcerebellum = 0.40 at 15 min p.i.). Furthermore, metabolism studies revealed a considerable uptake of radiometabolites of [18F]11 in the brain (66% parent fraction at 30 min p.i.). Altogether, despite the low specificity and the blood–brain barrier crossing of radiometabolites observed in vivo, [18F]11 is a valuable imaging probe for the in vitro investigation of PDE2A in the brain and has potential as a lead compound for further development of a PDE2A-specific PET ligand for neuroimaging.

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“…The above results indicated that monitoring of MAO-B changes in preclinical stages of Aβ accumulation could be achieved, and 23 had the potential to act as a surrogate marker of reactive astrogliosis in the AD continuum. More recently, novel 18 F-labeled radioligands 24 and 25 were developed based on indanone and safinamide, respectively, although the BBB-permeable radio-metabolites of the indanone derivative and multitarget character of the safinamide obstructed the further applications of these probes [50,51].…”

Section: Reversibly Binding Radiotracers For Monoamine Oxidase Amentioning

confidence: 99%

Small molecule probes for the specific imaging of monoamine oxidase A and monoamine oxidase B

Fang,

Chen,

Yang

2024

iRADIOLOGY

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Monoamine oxidases (MAOs) are a class of flavin enzymes that are mainly present in the outer membrane of mitochondria and play a crucial role in maintaining the homeostasis of monoamine neurotransmitters in the central nervous system. Furthermore, expression of MAOs is associated with the functions of peripheral organs. Dysfunction of MAOs is relevant in a variety of diseases such as neurodegenerative diseases, heart failure, metabolic disorders, and cancers. Monoamine oxidases have two isoenzymes, namely, monoamine oxidase A (MAO‐A) and monoamine oxidase B (MAO‐B). Therefore, the development of reliable and specific methods to detect these two isoenzymes is of great significance for the in‐depth understanding of their functions in biological systems, and for further promoting the clinical diagnosis and treatment of MAO‐related diseases. This review mainly focuses on the advances in small molecular probes for the specific imaging of MAO‐A and MAO‐B, including radiolabeled probes, fluorescent probes, and a 19F magnetic resonance imaging probe. In addition, applications of these probes for detecting MAO expression levels in cells, tissues, animal models, and patients are described. Finally, the challenges and perspectives of developing novel MAO imaging probes are also highlighted.

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In vitro and in vivo evaluation of fluorinated indanone derivatives as potential positron emission tomography agents for the imaging of monoamine oxidase B in the brain

Cited by 11 publications

References 48 publications

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

Radiosynthesis and Preclinical Evaluation of an 18F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A)

Small molecule probes for the specific imaging of monoamine oxidase A and monoamine oxidase B

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