In Vivo Imaging of Human Cholinergic Nerve Terminals with (–)-5-<sup>18</sup>F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses

Petrou, M.D. Ilya; Frey, Kirk A.; Kilbourn, Michael R.; Scott, Peter J. H.; Raffel, David M.; Bohnen, Nicolaas I.; Müller, Martijn; Albin, Roger L.; Koeppe, Robert A.

doi:10.2967/jnumed.113.124792

Cited by 112 publications

(121 citation statements)

References 15 publications

(16 reference statements)

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“…Similar affinity and selectivity have been found for (-)-FEOBV [125] , a radioligand first described in 1993 [126] and recently chosen for human VAChT studies [127] . Autoradiographic investigations of the human brain have revealed that region of patients with AD [128] .…”

Section: New Compoundssupporting

confidence: 66%

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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Section: New Compoundssupporting

confidence: 66%

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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“…Recently, the use of the cerebellum as the reference region for quantification of 123 I-iodobenzovesamicol SPECT data has been validated using an arterial input function (10). Furthermore, a recent study using a novel PET VAChT radiotracer has shown in healthy subjects similar levels of binding in the visual cortex and cerebellum as well as a differential cholinergic innervation within the cerebellum between the vermal region and the cerebellar hemispheres (11). This result challenges the statement that, from a cholinergic point of view, the occipital cortex is the most sparsely innervated region in the human brain.…”

Section: Discussioncontrasting

confidence: 55%

“…Even though the occipital cortex has been classically used as the reference region (9), use of the cerebellum was also recently proposed (10), and particularly the cerebellar hemispheres (11). 123 I-iodobenzovesamicol quantification with MRTM2 was successful in providing a better understanding of pathophysiology in neurologic disorders involving cholinergic impairment (5,6).…”

mentioning

confidence: 99%

Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with ¹²³I-Iodobenzovesamicol

et al. 2015

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123 I-iodobenzovesamicol is a SPECT radioligand selective for the vesicular acetylcholine transporter (VAChT) and used to assess the integrity of cholinergic pathways in various neurologic disorders. The current noninvasive method for quantitative analysis of 123 Iiodobenzovesamicol, based on multilinear reference tissue model 2 (MRTM2), requires repeated scans for several hours, limiting its application in clinical trials. Our objective was to validate a simplified acquisition method based on a single 123 I-iodobenzovesamicol static scan preserving the quantification accuracy. Three acquisition times were tested comparatively to a kinetic analysis using MRTM2. Methods: Six healthy volunteers underwent a dynamic SPECT acquisition comprising 14 frames over 28 h and an MR imaging scan. MR images were automatically segmented, providing the volumes of 19 regions of interest (ROIs). SPECT datasets were coregistered with MR images, and regional time-activity curves were derived. For each ROI, a complete MRTM2 pharmacokinetic analysis, using the cerebellar hemispheres as the reference region, led to the calculation of a 123 I-iodobenzovesamicol-to-VAChT binding parameter, the nondisplaceable binding potential (BP ND-MRTM2 ). A simplified analysis was also performed at 5, 8, and 28 h after injection, providing a simplified BP ND , given as BP ND-t 5 C ROI − C cerebellar hemispheres / C cerebellar hemispheres , with C being the averaged radioactive concentration. Results: No significant difference was found among BP ND-5 h , BP ND-8 h , and BP ND-MRTM2 in any of the extrastriatal regions explored. BP ND-28 h was significantly higher than BP ND-5 h , BP ND-8 h , and BP ND-MRTM2 in 9 of the 17 regions explored (P , 0.05). BP ND-5 h , BP ND-8 h , and BP ND-28 h correlated significantly with BP ND-MRTM2 (P , 0.05; ρ 5 0. 99, 0.98, and 0.92, respectively). In the striatum, BP ND-28 h was significantly higher than BP ND-5 h and BP ND-8 h . BP ND-5 h differed significantly from BP ND-MRTM2 (P , 0.05), with BP ND-5 h being 43.6% lower. Conclusion: In the extrastriatal regions, a single acquisition at 5 or 8 h after injection provides quantitative results similar to a pharmacokinetic analysis. However, with the highest correlation and accuracy, 5 h is the most suitable time to perform an accurate 123 I-iodobenzovesamicol quantification. In the striatum, none of the 3 times has led to an accurate quantification.

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“…While impaired attention, working memory capacity and executive function in PD-MCI have been mostly linked to fronto-striatal and mesocortical dopamine network deficits (Gratwicke et al, 2015;Cools et al, 2008), dementia in both AD and PD has been related to cholinergic network dysfunction (Ballinger et al, 2016;Bohnen et al, 2015Bohnen et al, , 2003Francis et al, 1999;Hilker et al, 2005;Perez-Lloret and Barrantes, 2016). Of note, cholinergic afferents are relatively enriched in frontal cortices (Petrou et al, 2014) and prefrontal projections to the nucleus basalis of Meynert may modulate cholinergic inputs to sensory cortices and thus represent another component of the top-down frontoparietal attention network (Gratwicke et al, 2015) (in addition to direct projections from frontoparietal cortices to extrastriate visual areas). In line with this notion, treatment with a cholinesterase inhibitor (ChEI) led to increased activation in prefrontal regions and improved attention and working memory in both AD-MCI (Rombouts et al, 2002;Saykin et al, 2004) and PD-MCI (Possin et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

[P3–382]: NEURAL EVIDENCE FOR DEFECTIVE TOP‐DOWN CONTROL OF VISUAL PROCESSING IN PARKINSON's AND ALZHEIMER's DISEASE

Rektorová

Elfmarková

Gajdoš

et al. 2017

Alzheimer's & Dementia

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Introduction:We used a functional MRI paradigm involving conventional vs. unconventional views of objects to assess bottom-up vs. top-down visual processing in Parkinson's disease (PD) with normal cognition, PD with mild cognitive impairment (MCI), and MCI due to Alzheimer's disease (AD) as compared to healthy controls. We particularly aimed at determining whether the task discriminated between PD with and without MCI and between two MCI groups due to distinct pathologies (AD and PD). Methods: 116 right-handed subjects (21 MCI due to AD; 16 PD with normal cognition; 24 PD with MCI; 55 healthy controls) performed a visual object-matching task in a T MR scanner. T statistic maps were computed to contrast task-based activation during unconventional vs. conventional view conditions. One-way ANOVAs and post hoc tests were performed to assess differences across and between groups. Results: Both MCI groups performed worse than controls in the unconventional views condition and showed reduced activation of right anterior cingulate cortex and right superior parietal lobule (PD with MCI), and right middle and inferior frontal gyri (MCI due to AD). Neural responses in cortical areas within the ventral and dorsal visual pathway appeared to be preserved in both MCI groups. Receiver operating characteristic analysis of MRI contrast in the right superior parietal lobule distinguished PD with and without MCI with 87.50% sensitivity and 86.98% specificity. Conclusions: Impaired recognition of objects presented in unconventional orientations in MCI due to PD and AD was associated with decreased activation of frontoparietal regions, consistent with defective top-down regulation of visual processing. Aberrant activation of superior parietal cortex may serve as an early imaging biomarker of impending cognitive impairment in PD.

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In Vivo Imaging of Human Cholinergic Nerve Terminals with (–)-5-¹⁸F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses

Cited by 112 publications

References 15 publications

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with ¹²³I-Iodobenzovesamicol

[P3–382]: NEURAL EVIDENCE FOR DEFECTIVE TOP‐DOWN CONTROL OF VISUAL PROCESSING IN PARKINSON's AND ALZHEIMER's DISEASE

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In Vivo Imaging of Human Cholinergic Nerve Terminals with (–)-5-18F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses

Cited by 112 publications

References 15 publications

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with 123I-Iodobenzovesamicol

[P3–382]: NEURAL EVIDENCE FOR DEFECTIVE TOP‐DOWN CONTROL OF VISUAL PROCESSING IN PARKINSON's AND ALZHEIMER's DISEASE

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In Vivo Imaging of Human Cholinergic Nerve Terminals with (–)-5-¹⁸F-Fluoroethoxybenzovesamicol: Biodistribution, Dosimetry, and Tracer Kinetic Analyses

Simplified Quantification Method for In Vivo SPECT Imaging of the Vesicular Acetylcholine Transporter with ¹²³I-Iodobenzovesamicol