Synthesis and Preliminary Evaluation of Phenyl 4-<sup>123</sup>I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology

Macdonald, Ian R.; Reid, G. Andrew; Pottie, Ian R.; Martin, Earl; Darvesh, Sultan

doi:10.2967/jnumed.115.162032

Cited by 12 publications

(12 citation statements)

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“…Additionally, decreased uptake of this radioligand in the AD brain compared to the normal brain was observed, contradicting histochemical and isolation studies of BChE [30, 31, 34–36]. Recently, more promising progress has been observed with a cholinesterase radioligand, phenyl 4-[ 123 I]iodophenylcarbamate, that was able to distinguish cortical AD Aβ plaques from those found in NwAβ in autoradiographic studies [42]. In addition, a specific BChE radiotracer has been shown to distinguish the 5XFAD mouse model [88] from its wild-type counterpart using single-photon emission computed tomography imaging studies [89, 90].…”

Section: Discussionmentioning

confidence: 99%

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Macdonald

Maxwell

Reid

et al. 2017

JAD

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Amyloid-β (Aβ) plaques are a neuropathological hallmark of Alzheimer’s disease (AD); however, a significant number of cognitively normal older adults can also have Aβ plaques. Thus, distinguishing AD from cognitively normal individuals with Aβ plaques (NwAβ) based on Aβ plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Aβ, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n = 8), NwAβ (n = 6), cognitively normal without plaques (n = 8), and other common dementias including corticobasal degeneration, frontotemporal dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Aβ and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Aβ and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAβ and AD, due to the virtual absence of BChE-associated plaques in NwAβ brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUC = 1.0, sensitivity/specificity = 100% /100%) when compared to Aβ (AUC = 0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.

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Section: Discussionmentioning

confidence: 99%

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Macdonald

Maxwell

Reid

et al. 2017

JAD

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“…More importantly, these findings are in keeping with earlier observations in human AD that BChE associates with AD pathology [23] , [35] , [36] , [37] . Evidence that BChE radiotracers can distinguish between AD pathology and that in cognitively normal brains with pathology bodes well for increased diagnostic performance with the development of selective BChE targeted imaging agents for comparative studies focused on the cerebral cortex [39] .…”

Section: Discussionmentioning

confidence: 99%

“…A recent autoradiographic study [39] , using a cholinesterase radioligand, phenyl 4-[ 123 I]iodophenylcarbamate, was able to distinguish AD amyloid plaques from those found in the cerebral cortex of cognitively normal brains. However, in further in vivo studies, this radiotracer did not provide satisfactory brain retention.…”

Section: Introductionmentioning

confidence: 99%

“…However, in further in vivo studies, this radiotracer did not provide satisfactory brain retention. Prospective substrate-type 123 I SPECT radioligands containing the N -methylpiperidinol moiety were designed to prolong ligand-enzyme latencies [39] , [40] . Ex vivo autoradiographic evidence was earlier reported for N -methylpiperidin-4yl 4-[ 123 I]iodobenzoate, which, injected intravenously into a rat, entered the brain and labeled areas known to exhibit BChE activity in histochemical studies [40] .…”

Section: Introductionmentioning

confidence: 99%

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Targeting butyrylcholinesterase for preclinical single photon emission computed tomography (SPECT) imaging of Alzheimer's disease

DeBay

Reid

Pottie

et al. 2017

A&D Transl Res & Clin Interv

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IntroductionDiagnosis of Alzheimer's disease (AD) in vivo, by molecular imaging of amyloid or tau, is constrained because similar changes can be found in brains of cognitively normal individuals. Butyrylcholinesterase (BChE), which becomes associated with these structures in AD, could elevate the accuracy of AD diagnosis by focusing on BChE pathology in the cerebral cortex, a region of scant BChE activity in healthy brain.MethodsN-methylpiperidin-4-yl 4-[123I]iodobenzoate, a BChE radiotracer, was injected intravenously into B6SJL-Tg(APPSwFlLon, PSEN1∗M146 L∗L286 V) 6799Vas/Mmjax (5XFAD) mice and their wild-type (WT) counterparts for comparative single photon emission computed tomography (SPECT) studies. SPECT, computed tomography (CT), and magnetic resonance imaging (MRI) enabled comparison of whole brain and regional retention of the BChE radiotracer in both mouse strains.ResultsRetention of the BChE radiotracer was consistently higher in the 5XFAD mouse than in WT, and differences were particularly evident in the cerebral cortex.DiscussionCerebral cortical BChE imaging with SPECT can distinguish 5XFAD mouse model from the WT counterpart.

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“… 48 Specific imaging of BChE is a new area of interest, and recently agents specifically targeting BChE have been reported. 49 , 50 …”

Section: Ec 31: Esterasesmentioning

confidence: 99%

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

2017

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Hydrolytic enzymes are a large class of biological catalysts that play a vital role in a plethora of critical biochemical processes required to maintain human health. However, the expression and/or activity of these important enzymes can change in many different diseases and therefore represent exciting targets for the development of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radiotracers. This review focuses on recently reported radiolabeled substrates, reversible inhibitors, and irreversible inhibitors investigated as PET and SPECT tracers for imaging hydrolytic enzymes. By learning from the most successful examples of tracer development for hydrolytic enzymes, it appears that an early focus on careful enzyme kinetics and cell-based studies are key factors for identifying potentially useful new molecular imaging agents.

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Synthesis and Preliminary Evaluation of Phenyl 4-¹²³I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology

Cited by 12 publications

References 36 publications

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Targeting butyrylcholinesterase for preclinical single photon emission computed tomography (SPECT) imaging of Alzheimer's disease

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

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Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology

Cited by 12 publications

References 36 publications

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease

Targeting butyrylcholinesterase for preclinical single photon emission computed tomography (SPECT) imaging of Alzheimer's disease

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

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Product

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Synthesis and Preliminary Evaluation of Phenyl 4-¹²³I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology