A Comparative Study of <i>in vitro</i> Assays for Predicting the Nonspecific Binding of PET Imaging Agents <i>in vivo</i>

Gobbi, Luca; Mercier, Joël; Bang‐Andersen, Benny; Nicolas, Jean‐Marie; Reilly, John M.; Wagner, Björn; Whitehead, David M.; Briard, Emmanuelle; Maguire, R. Paul; Borroni, Edilio; Auberson, Yves P.

doi:10.1002/cmdc.201900608

Cited by 9 publications

(16 citation statements)

References 43 publications

(40 reference statements)

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“…On top of its significant role in mediating brain penetration, lipophilicity, frequently approximated by logD measurements, is an important metric in the context of PET tracer development as it allows for the preliminary assessment of the extent of NDB to be expected. While the correlation of logD and NDB is weak at best [ 14 , 15 ], certain hard lipophilicity cutoffs, e.g., shake-flask logD < 3.5, continue to be successfully employed in PET tracer development [ 16 ]. However, the design of brain-penetrable PET tracers displaying low NDB is a multiparameter optimization effort: relying too much on individual physicochemical parameters may be misleading since it does not give a full picture.…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

et al. 2022

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The muscarinic acetylcholine receptor family is a highly sought-after target in drug and molecular imaging discovery efforts aimed at neurological disorders. Hampered by the structural similarity of the five subtypes’ orthosteric binding pockets, these efforts largely failed to deliver subtype-selective ligands. Building on our recent successes with arecaidine-derived ligands targeting M1, herein we report the synthesis of a related series of 11 hydroxylated arecaidine esters. Their physicochemical property profiles, expressed in terms of their computationally calculated CNS MPO scores and HPLC-logD values, point towards blood–brain barrier permeability. By means of a competitive radioligand binding assay, the binding affinity values towards each of the individual human mAChR subtypes hM1–hM5 were determined. The most promising compound of this series 17b was shown to have a binding constant towards hM1 in the single-digit nanomolar region (5.5 nM). Similar to our previously reported arecaidine-derived esters, the entire series was shown to act as hM1R antagonists in a calcium flux assay. Overall, this study greatly expanded our understanding of this recurring scaffolds’ structure–activity relationship and will guide the development towards highly selective mAChRs ligands.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

et al. 2022

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“…The data in Table 2 revealed that both radioligands had a high PPB level, but [ 18 F]F-IV is associated with proteins to a greater extent than [ 11 C]MPbP: >98 vs. 92% for rats and >99 vs. 98% for humans, respectively. The measured high PPB of [ 18 F]F-IV appears to be responsible for the high level of radioactivity in the blood, its retention in rat tissues, and for lower brain uptake (compared to MPbP) in LPS-treated rats, [34]. In this study, we did not evaluate the contribution of non-specific binding or off-target interactions of [ 18 F]F-IV with proteins and phospholipids in the brain.…”

Section: Plasma Protein Binding (Ppb) For [ 18 F]f-iv and [ 11 C]mpbpmentioning

confidence: 91%

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

et al. 2021

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Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [11C]MPbP (4′-[11C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [18F]F-IV in a rodent model of neuroinflammation. [18F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by 18F-fluoroethylation of the precursor with Boc-protecting group (15) with [18F]2-fluoro-1-bromoethane ([18F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [18F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [11C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [18F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia.

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“…Bearing the potential application of the designed carbamates as central nervous system PET tracers in mind, we opted to evaluate selected physico-chemical properties, such as lipophilicity, serving as approximate surrogate measures of NDB and blood-brain bar rier (BBB) permeability. Although the predictive power of, for example, logP or logD, for NDB or BBB penetration is critically debated, their influence on the aforementioned phe nomena is undisputed [26][27][28][29].…”

Section: Physico-chemical Property Profile and Stabilitymentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

et al. 2022

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Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4’-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM1-hM5, the most promising compound 2 displayed a high binding affinitiy towards hM1R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM2-5R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development.

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A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo

Cited by 9 publications

References 43 publications

Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs

Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging

Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

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