Phase 1 Study of the Pittsburgh Compound B Derivative <sup>18</sup>F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease

Nelissen, Natalie; Laere, Koen Van; Thurfjell, Lennart; Owenius, Rikard; Vandenbulcke, Mathieu; Koole, Michel; Bormans, Guy; Brooks, David J.; Vandenberghe, Rik

doi:10.2967/jnumed.109.063305

Cited by 283 publications

(250 citation statements)

References 38 publications

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“…20,27 For amyloid radioligands, the overestimation by quasi-steady-state SUVR has been estimated to be 30% to 70%. [22][23][24]26 A further property of the quasi-steady-state SUVR value is that the overestimation is sensitive to absolute or relative changes in regional cerebral blood flow (rCBF). For amyloid imaging, such an effect has recently been suggested from recent experimental data with […”

Section: Introductionmentioning

confidence: 99%

“…20,21 This phase is characterized by a gradual wash-out of radioactivity from both target and reference regions and the time curve for the ratio of radioactivity between target and reference regions is almost stable though with a slight positive slope for several radioligands. [22][23][24][25][26] The SUVR value is viewed as an index for specific binding and its proportionality to the distribution volume ratio (DVR), obtained using fully quantitative PET acquisition and analysis, has been shown for several amyloid radioligands. [22][23][24]26 However, the quasi-steady-state SUVR values are biased in the sense that they overestimate DVR as the time window of acquisition occurs after the peak time of specific binding.…”

Section: Introductionmentioning

confidence: 99%

“…[22][23][24][25][26] The SUVR value is viewed as an index for specific binding and its proportionality to the distribution volume ratio (DVR), obtained using fully quantitative PET acquisition and analysis, has been shown for several amyloid radioligands. [22][23][24]26 However, the quasi-steady-state SUVR values are biased in the sense that they overestimate DVR as the time window of acquisition occurs after the peak time of specific binding. 20,27 For amyloid radioligands, the overestimation by quasi-steady-state SUVR has been estimated to be 30% to 70%.…”

Section: Introductionmentioning

confidence: 99%

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Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

Cselényi

Farde

2015

J Cereb Blood Flow Metab

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Longitudinal positron emission tomography (PET) imaging of beta-amyloid is used in basic research and in drug efficacy trials in Alzheimer's disease (AD). However, the extent of amyloid accumulation after clinical onset is not fully known. Importantly, regional PET data are typically quantified using the standardized uptake value ratio (SUVR), which according to simulations is sensitive to changes in regional cerebral blood flow (rCBF). We aimed to better understand the potentials of longitudinal amyloid imaging by disentangling the influence of blood flow on SUVR using experimental data.[18F]AV-45 PET data from 101 subjects, ranging from cognitively normal to AD patients, in the Alzheimer's Disease Neuroimaging Initiative were extracted. The relationship between global cortical distribution volume ratio, indicator of rCBF (R1), and SUVR was examined using multilinear regression. There was a significant effect of rCBF on SUVR. The effect increased by disease severity. Results suggest that changes in rCBF can produce apparent changes in SUVR in AD. Therefore, future longitudinal studies should measure amyloid changes in a way not sensitive to this effect, ideally using quantitative PET imaging. Furthermore, the results suggest no true accumulation beyond clinical onset and highlight the risks of longitudinal amyloid imaging in drug trials in AD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

Cselényi

Farde

2015

J Cereb Blood Flow Metab

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“…PET imaging ligands including Pittsburgh compound B ( 11 C-PIB) [2], 18 F-florbetaben [3], 18 F-flutemetamol [4] and 18 F-florbetapir [5] have been developed for estimation of cortical beta amyloid (Aβ) neuritic plaque deposition, a hallmark pathology, and a required element for the evaluation of neuropathological changes in patients with Alzheimer's disease (AD) [6]. As shown by their respective package inserts/summaries of product characteristics, as well as the published literature [7][8][9], reader accuracy in the pivotal trials for the 18 F-labeled agents averaged close to 90% for discriminating patients found at autopsy to have no or sparse neuritic plaques (amyloid-negative, Aβ−) from those found to have moderate to frequent plaques (amyloid-positive, Aβ+).…”

Section: Introductionmentioning

confidence: 99%

Quantitation of PET signal as an adjunct to visual interpretation of florbetapir imaging

Pontecorvo

Arora

Devine

et al. 2017

Eur J Nucl Med Mol Imaging

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Purpose This study examined the feasibility of using quantitation to augment interpretation of florbetapir PET amyloid imaging. Methods A total of 80 physician readers were trained on quantitation of florbetapir PET images and the principles for using quantitation to augment a visual read. On day 1, the readers completed a visual read of 96 scans (46 autopsy-verified and 50 from patients seeking a diagnosis). On day 2, 69 of the readers reinterpreted the 96 scans augmenting their interpretation with quantitation (VisQ method) using one of three commercial software packages. A subset of 11 readers reinterpreted all scans on day 2 based on a visual read only (VisVis control). For the autopsy-verified scans, the neuropathologist's modified CERAD plaque score was used as the truth standard for interpretation accuracy. Because an autopsy truth standard was not available for scans from patients seeking a diagnosis, the majority VisQ interpretation of the three readers with the best accuracy in interpreting autopsy-verified scans was used as the reference standard. Results Day 1 visual read accuracy was high for both the autopsy-verified scans (90%) and the scans from patients seeking a diagnosis (87.3%). Accuracy improved from the visual read to the VisQ read (from 90.1% to 93.1%, p < 0.0001).Importantly, access to quantitative information did not decrease interpretation accuracy of the above-average readers (>90% on day 1). Accuracy in interpreting the autopsy-verified scans also increased from the first to the second visual read (VisVis group). However, agreement with the reference standard (best readers) for scans from patients seeking a diagnosis did not improve with a second visual read, and in this cohort the VisQ group was significantly improved relative to the VisVis group (change 5.4% vs. −1.1%, p < 0.0001). Conclusion These results indicate that augmentation of visual interpretation of florbetapir PET amyloid images with quantitative information obtained using commercially available software packages did not reduce the accuracy of readers who were already performing with above average accuracy on the visual read and may improve the accuracy and confidence of some readers in clinically relevant cases.

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“…Flutametamol was developed by GE Healthcare, under the brand name Vizamyl. This compound is similar to PIB and hence has structural similarities to Thioflavin-S. Flutemetamol was initially shown in phase I trials to have a good safety profile with affinity to Aβ and increased cortical-to-cerebellar uptake in a small samples size of 8 patients with clinically probable AD and 8 healthy controls [30]. Phase II trials demonstrated 25 of 27 patients with clinical AD having amyloid-positive scans, and 1 of 15 control patients having a positive scan corresponding to a sensitivity and specificity of 93.1 % and 93.3 %, respectively.…”

Section: [ 18 F]3'-f-pib or Flutemetamolmentioning

confidence: 99%

Amyloid Imaging: Poised for Integration into Medical Practice

Anand

Sabbagh

2017

Neurotherapeutics

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Amyloid imaging represents a significant advance as an adjunct in the diagnosis of Alzheimer's disease (AD) because it is the first imaging modality that identifies in vivo changes known to be associated with the pathogenesis. Initially, 11 C-PIB was developed, which was the prototype for many 18 F compounds, including florbetapir, florbetaben, and flutemetamol, among others. Despite the high sensitivity and specificity of amyloid imaging, it is not commonly used in clinical practice, mainly because it is not reimbursed under current Center for Medicare and Medicaid Services guidelines in the USA. To guide the field in who would be most appropriate for the utility of amyloid positron emission tomography, current studies are underway [Imaging Dementia Evidence for Amyloid Scanning (IDEAS) Study] that will inform the field on the utilization of amyloid positron emission tomography in clinical practice. With the advent of monoclonal antibodies that specifically target amyloid antibody, there is an interest, possibly a mandate, to screen potential treatment recipients to ensure that they are suitable for treatment. In this review, we summarize progress in the field to date.

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Phase 1 Study of the Pittsburgh Compound B Derivative ¹⁸F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease

Cited by 283 publications

References 38 publications

Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

Quantitation of PET signal as an adjunct to visual interpretation of florbetapir imaging

Amyloid Imaging: Poised for Integration into Medical Practice

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Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease

Cited by 283 publications

References 38 publications

Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

Quantification of Blood Flow-Dependent Component in Estimates of Beta-Amyloid Load Obtained Using Quasi-Steady-State Standardized Uptake Value Ratio

Quantitation of PET signal as an adjunct to visual interpretation of florbetapir imaging

Amyloid Imaging: Poised for Integration into Medical Practice

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Product

Resources

About

Phase 1 Study of the Pittsburgh Compound B Derivative ¹⁸F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease