Synthesis and preliminary evaluation of [18F]FEtP4A, a promising PET tracer for mapping acetylcholinesterase in vivo

Zhang, Ming‐Rong; Tsuchiyama, Akio; Haradahira, Terushi; Furutsuka, Kenji; Yoshida, Yuichiro; Noguchi, Takayo Kida Junko; Irie, Toshiaki; Suzuki, Kazutoshi

doi:10.1016/s0969-8051(01)00315-8

Cited by 23 publications

(10 citation statements)

References 22 publications

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“…N ‐[ 18 F]Fluoroethylpiperidin‐4‐yl acetate ([ 18 F]FEtP4A) was therefore synthesized as an [ 18 F]fluoroethylated MP4A derivative (Scheme ) . The N ‐[ 18 F]fluoroethyl derivative of [ 11 C]MP4A/P can be prepared by N ‐[ 18 F]fluoroethylation of piperidinol ester using [ 18 F]fluoroethyl bromide, [ 18 F]fluoroethyl iodide (generated in situ by the addition of NaI to [ 18 F]fluoroethyl bromide), [ 18 F]fluoroethyl triflate, or [ 18 F]fluoroethyl tosylate (not isolated from ethylene glycol ditosylate) . The efficiency of the [ 18 F]fluoroethylation with [ 18 F]fluoroethyl bromide and [ 18 F]fluoroethyl tosylate was relatively low even at high reaction temperature (~130 °C).…”

Section: Design and Preparation Of [18f]fetp4a And [18f]fep‐4mamentioning

confidence: 99%

PET probes for imaging brain acetylcholinesterase

Kikuchi¹,

Okamura²,

Zhang³

et al. 2013

Labelled Comp Radiopharmac

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Imaging acetylcholinesterase (AChE) is valuable not only for diagnosing and understanding dementia but also for monitoring the effects of cholinesterase inhibitors used as antidementia drugs and for determining the appropriate clinical dosage of newly developed cholinesterase inhibitors. The distribution of AChE in the living brain can be imaged with two different types of radioprobes, including substrate-type and ligand-type probes. The substrate-type positron emission tomography (PET) probes, N-[(11) C]methylpiperidin-4-yl acetate ([(11) C]MP4A), and its propionate, [(11) C]MP4P, have been widely used in clinical studies of dementia, including Alzheimer's disease. [(11) C]MP4A and [(11) C]MP4P have been used to demonstrate a reduction in AChE activity in the brains of dementia patients, as well as the bioavailability of AChE inhibitors, leading to the subsequent development of the widely available (18) F-labeled derivatives of MP4A. In addition, several radiolabeled cholinesterase inhibitors have been developed as PET probes for AChE mapping in the brain. Herein, we have reviewed the development of PET probes for the imaging of AChE in the brain and described the principles of measuring AChE activity in the brain using PET with substrate-type radioprobes. A discussion of the reagents developed from substrate-type PET probes for the specific measurement of AChE activity in vitro has also been provided.

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Section: Design and Preparation Of [18f]fetp4a And [18f]fep‐4mamentioning

confidence: 99%

PET probes for imaging brain acetylcholinesterase

Kikuchi¹,

Okamura²,

Zhang³

et al. 2013

Labelled Comp Radiopharmac

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“…Subsequently, many researchers continued to perform the prepa-ration of [ 18 [9], in our facility, we have produced about much than ten [ 18 F]fluoroethyl ligands via [ 18 F]FCH 2 CH 2 Br for animal evaluation using the automatic system [31][32][33][34], some of which are being used for clinical investigation 2-3 times a week [35,36].…”

Section: [ 18 F]fch 2 Ch 2 Brmentioning

confidence: 99%

[18F]Fluoroalkyl Agents: Synthesis, Reactivity and Application for Development of PET Ligands in Molecular Imaging

Zhang¹,

Suzuki²

2007

CTMC

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Fluorine-18 ((18)F, beta(+); 96.7%, T(1/2)=109.8 min) is of considerable importance for developing positron emission tomography (PET) ligands for imaging receptor, enzyme, gene expression etc. in brain, tumor, myocardium and other regions or organs due to its optimal decay characteristics. To synthesize (18)F-labeled PET ligands, reliable labeling techniques inserting (18)F into a target molecule are necessary. [(18)F]Fluoroalkylation is a useful way of introducing (18)F into target molecules containing amino, phenol, thiophenol, and amide functional groups. Here, we review the preparation, reactivity and application of [(18)F]fluoroalkyl agents for the development of (18)F-labeled PET ligands in molecular imaging. [(18)F]Fluoroalkyl agents have been synthesized by reacting [(18)F]F(-) with the corresponding alkyl derivatives containing halogen and sulfonate as leaving groups. After the fluorination reaction, the radiolabeled products with relatively low boiling points were distilled from the reaction mixtures, sometimes added by Sep-Pak or gas chromatography separation. The [(18)F]fluoromethyl agents have high reactivity with nucleophilic substrates, but many [(18)F]fluoromethylated compounds are in vitro unstable. To increase the efficiency of [(18)F]fluoroethylation, [(18)F]FCH2CH2Br, the most frequently used [(18)F]fluoroethyl agent, was converted into [(18)F]FCH2CH2I or [(18)F]FCH2CH2OTf in situ. Most [(18)F]fluoromethylated ligands were found to be in vivo unstable due to defluorination. Deuterium substitution for the fluoromethyl group reduced defluorination to an extent. A number of [(18)F]fluoroethylated PET ligands have been developed for animal evaluation and clinical investigation.

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“…18 F-labeled derivatives of MP4A and MP4P would have advantages such as possibility of long-distance transportation and preparation of the radioprobe batches for multiple patients due to the longer half-life ( 18 F, 110 min; 11 C, 20 min) of 18 F compared to 11 C. Though change of the N-[ 11 C]methyl group in MP4A or MP4P by the [ 18 F]fluoromethyl group would produce minimum biochemical change, it is not applicable to the piperidine or pyrrolidine ring due to instability of the fluoromethyl group attached to the secondary amine [77] and unfavorable effect of fluorine ion on AChE activity [78]. [79]. Though [ 18 F]FEtP4A which has N-fluoroethyl moiety was resistant to in vivo defluorination, the compound showed a much lower specificity for AChE (71%) than that of MP4A (96%) and approximately one-twentieth of reactivity for AChE compared to MP4A in rat cerebral cortical homogenate and pure enzyme [79] ( Table 5).…”

Section: [ 11 C]acetylcholine Analogsmentioning

confidence: 99%

“…[79]. Though [ 18 F]FEtP4A which has N-fluoroethyl moiety was resistant to in vivo defluorination, the compound showed a much lower specificity for AChE (71%) than that of MP4A (96%) and approximately one-twentieth of reactivity for AChE compared to MP4A in rat cerebral cortical homogenate and pure enzyme [79] ( Table 5). These results suggest that we use [ 18 F]FEtP4A for measurement of high AChE activity regions such as cerebellum rather than cerebral cortex.…”

Section: [ 11 C]acetylcholine Analogsmentioning

confidence: 99%

Cerebral Acetylcholinesterase Imaging: Development of the Radioprobes

Kikuchi¹,

Okamura²,

Fukushi³

et al. 2007

CTMC

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Cerebral acetylcholinesterase (AChE) imaging is not only useful for diagnosis of dementia disorders but also for therapeutic monitoring of the effects of cholinesterase (ChE) inhibitors and for decision of the appropriate clinical dosage of newly developed ChE inhibitors. Several ChE inhibitors or the derivatives such as 1,2,3,4-tetrahydro-9-methylaminoacridine (MTHA), donepezil, physostigmine, CP126,998 and 2-fluoro-CP118,954 have been labeled with positron emitters for mapping cerebral AChE by positron emission tomography (PET). When [(11)C]MTHA or [(11)C]donepezil was injected in animals, the uptake poorly reflect the regional distribution of AChE in the brain because of high non-specific binding and/or less specific to AChE in vivo in the brain tissue. [(11)C]physostigmine, [(11)C]CP126,998 and 2-[(18)F]fluoro-CP118,954 were distributed corresponding well to the regional AChE activity in animals, and also former two probes were successfully applied to clinical PET trial. The other approach is measuring cerebral AChE activity with radiolabeled acetylcholine analogue substrates. We have developed the principle for measuring cerebral enzyme activity by PET and radiolabeled N-methylpiperidinyl esters for quantitative measurement of cerebral AChE activity. N-[(11)C]methylipiperidin-4-yl acetate (MP4A) and N-[(11)C]methylpiperidin-4-yl propionate (MP4P) have been used for clinical studies of other demented disorders including Alzheimer's disease (AD), and the probes have demonstrated not only the reduction of AChE activity in the cerebral cortex of patients with AD but also the inhibitory effects of donepezil and rivastigmine on AChE activity in the brain of AD patients. Following this succession, widely available [(18)F]-labeled derivatives of MP4A and MP4P have been developed based on the structure-activity relationships between AChE and piperidinol esters.

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Synthesis and preliminary evaluation of [18F]FEtP4A, a promising PET tracer for mapping acetylcholinesterase in vivo

Cited by 23 publications

References 22 publications

PET probes for imaging brain acetylcholinesterase

PET probes for imaging brain acetylcholinesterase

[18F]Fluoroalkyl Agents: Synthesis, Reactivity and Application for Development of PET Ligands in Molecular Imaging

Cerebral Acetylcholinesterase Imaging: Development of the Radioprobes

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