High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) Ready for Animal or Human Administration

Liu, Jie; Kepe, Vladimir; Žabjek, Alenka; Petrič, Andrej; Padgett, Henry C.; Satyamurthy, Nagichettiar; Barrio, Jorge R.

doi:10.1007/s11307-006-0061-4

Cited by 68 publications

(58 citation statements)

References 30 publications

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“…1), also an excellent staining dye in vitro, is capable of crossing the blood-brain barrier. The fluorinated DDNP analog, 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene) (FDDNP), can be synthesized with the 18 F positron emitter and was used as the first molecular imaging probe for the regional assessment of Aβ and tau deposition in the brains of living AD patients (2)(3)(4)(5).…”

Section: Dicyanovinylnaphthalenes For Neuroimaging Of Amyloids and Rementioning

confidence: 99%

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Petrič

Johnson

Pham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The positron-emission tomography (PET) probe 2-(1-[6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene) (FDDNP) is used for the noninvasive brain imaging of amyloid-β (Aβ) and other amyloid aggregates present in Alzheimer’s disease and other neurodegenerative diseases. A series of FDDNP analogs has been synthesized and characterized using spectroscopic and computational methods. The binding affinities of these molecules have been measured experimentally and explained through the use of a computational model. The analogs were created by systematically modifying the donor and the acceptor sides of FDDNP to learn the structural requirements for optimal binding to Aβ aggregates. FDDNP and its analogs are neutral, environmentally sensitive, fluorescent molecules with high dipole moments, as evidenced by their spectroscopic properties and dipole moment calculations. The preferred solution-state conformation of these compounds is directly related to the binding affinities. The extreme cases were a nonplanar analog t -butyl-FDDNP, which shows low binding affinity for Aβ aggregates (520 nM K i ) in vitro and a nearly planar tricyclic analog cDDNP, which displayed the highest binding affinity (10 pM K i ). Using a previously published X-ray crystallographic model of 1,1-dicyano-2-[6-(dimethylamino)naphthalen-2-yl]propene (DDNP) bound to an amyloidogenic Aβ peptide model, we show that the binding affinity is inversely related to the distortion energy necessary to avoid steric clashes along the internal surface of the binding channel.

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Section: Dicyanovinylnaphthalenes For Neuroimaging Of Amyloids and Rementioning

confidence: 99%

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Petrič

Johnson

Pham

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Then, 2 M HCl was added to the solution, followed by an additional 3-min reaction for deprotection of the hydroxyl group. After neutralization with 4 M AcOK, the product was purified by semipreparative high-performance liquid chromatography (HPLC) 18 F-THK-523 and 18 F-FDDNP were also prepared in a manner similar to the one described above using the corresponding tosylate precursors reported previously (15,25,26). 11 C-PiB was radiolabeled using its precursor (2-(4-aminophenyl)-6-methoxymethoxybenzothiazole) and 11 C-methyl triflate, as previously described (27).…”

Section: Synthesis and Radiosynthesis Of 2-arylquinoline Derivativesmentioning

confidence: 99%

Novel ¹⁸F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

et al. 2013

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Neurofibrillary tangles in Alzheimer disease (AD) brains are composed of the microtubule-associated protein tau. Noninvasive monitoring of tau protein aggregates in the living brain will provide useful information regarding tau pathophysiology in AD. However, no PET probes are currently available for selective detection of tau pathology in AD. We have previously reported 18 F-labeled THK-523 ( 18 F-6-(2-fluoroethoxy)-2-(4-aminophenyl)quinoline) as a tau imaging radiotracer candidate for PET. After compound optimization, we developed novel 18 F-labeled arylquinoline derivatives, 18 F-THK-5105 and 18 F-THK-5117, for use as tau imaging PET tracers. Methods: 18 F-labeled compounds were prepared from the corresponding tosylated precursors. The binding affinity of compounds to synthetic tau aggregates and tau-rich AD brain homogenates was determined by saturation and competition binding assays. The binding selectivity of compounds to tau pathology was evaluated by autoradiography of AD brain sections. The pharmacokinetics of compounds were assessed in biodistribution studies in normal mice. A 14-d toxicity study with intravenous administration of compounds was performed using rats and mice. Results: In vitro binding assays demonstrated higher binding affinity of THK-5105 and THK-5117 than THK-523 to tau protein aggregates and tau-rich AD brain homogenates. Autoradiographic analyses of AD brain sections showed that these radiotracers preferentially bound to neurofibrillary tangles and neuropil threads, which colocalized with Gallyas-positive and immunoreactive tau protein deposits. The distribution of this radiotracer binding in AD brain sections was completely different from that of 11 C-Pittsburgh compound B, showing preferential binding to amyloid plaques. Furthermore, these derivatives demonstrated abundant initial brain uptake and faster clearance in normal mice than 18 F-THK-523 and other reported 18 F-labeled radiotracers. THK-5105 and THK-5117 showed no toxic effects related to the administration of these compounds in mice and rats and no significant binding for various neuroreceptors, ion channels, and transporters at 1-mM concentrations. Conclusion: 18 Flabeled THK-5105 and THK-5117 are promising candidates as PET tau imaging radiotracers.

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“…[9] A detailed description of the synthesis of [ 18 F]FDDNP was only reported in 2006, by Barrio's group, together with its improved automated radiosynthesis. [11] The synthesis of the cold FDDNP started with commercially available 1-(6-methoxy-2-naphthyl)ethan-1-one (1), which was converted into ketone 2 by demethylation in hydrochloric acid (37 %) at reflux (Scheme 1). A Bucherer reaction between 2 and 2-(methylamino)ethanol, followed by a Knoevenagel condensation between the resulting amine derivative 3 and maScheme 1.…”

Section: Naphthalene Derivativesmentioning

confidence: 99%

“…In the past few years, a plethora of 11 C-and 18 F-labeled compounds have been synthesized and evaluated and some of them have undergone clinical trials to assess their potential for in vivo diagnosis of AD. Labeling with 11 C frequently involves the introduction of a […”

Section: Introductionmentioning

confidence: 99%

A Synthetic Overview of Radiolabeled Compounds for β‐Amyloid Targeting

Morais¹,

Paulo²,

Santos³

2011

Eur J Org Chem

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The formation of β‐amyloid plaques is considered a histopathological hallmark of Alzheimer's disease (AD), a neurodegenerative disorder that affects millions of people worldwide. For effective treatment of AD, diagnosis at an earlier stage of the degenerative process is essential. Therefore, in the last few years significant efforts to find probes for in vitro and/or in vivo imaging of β‐amyloid deposits have been made. This work presents an overview of different small molecules explored as fluorescent or radioactive probes for targeting β‐amyloid deposits. It focuses mainly on the different synthetic approaches used for their synthesis or radiosynthesis but their biological behaviour is also briefly discussed when appropriate.

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High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) Ready for Animal or Human Administration

Cited by 68 publications

References 30 publications

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Novel ¹⁸F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

A Synthetic Overview of Radiolabeled Compounds for β‐Amyloid Targeting

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High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) Ready for Animal or Human Administration

Cited by 68 publications

References 30 publications

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Dicyanovinylnaphthalenes for neuroimaging of amyloids and relationships of electronic structures and geometries to binding affinities

Novel 18F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease

A Synthetic Overview of Radiolabeled Compounds for β‐Amyloid Targeting

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Product

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Novel ¹⁸F-Labeled Arylquinoline Derivatives for Noninvasive Imaging of Tau Pathology in Alzheimer Disease