Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain

Zhang, Lei; Chen, Laigao; Dutra, Jason K.; Beck, Elizabeth M.; Nag, Sangram; Takano, Akihiro; Amini, Nahid; Arakawa, Ryosuke; Brodney, Michael A.; Buzon, Leanne; Doran, Shawn D.; Lanyon, Lorraine F.; McCarthy, Timothy J.; Bales, Kelly R.; Nolan, Charles E.; O’Neill, Brian T.; Schildknegt, Klaas; Halldin, Christer; Villalobos, Anabella

doi:10.1021/acs.jmedchem.7b01769

Cited by 17 publications

(24 citation statements)

References 32 publications

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“…PF-06684511 has been identified and evaluated as a novel candidate PET ligand that binds to the BACE1 target (half-maximal inhibitory concentration, 0.7 nM) (13). On radiolabeling with 18 F, it demonstrated favorable brain uptake and high binding specificity in nonhuman primates (NHPs) with PET imaging, suggesting it is a promising PET ligand for imaging BACE1 (13). In this research, 3 studies were performed.…”

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confidence: 99%

Quantitative Analysis of ¹⁸F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

et al. 2018

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β-secretase 1 (BACE1) is a key enzyme in the generation of β-amyloid, which is accumulated in the brain of Alzheimer disease patients. PF-06684511 was identified as a candidate PET ligand for imaging BACE1 in the brain and showed high specific binding in an initial assessment in a nonhuman primate (NHP) PET study using 18 F-PF-06684511. In this effort, we aimed to quantitatively evaluate the regional brain distribution of 18 F-PF-06684511 in NHPs under baseline and blocking conditions and to assess the target occupancy of BACE1 inhibitors. In addition, NHP whole-body PET measurements were performed to estimate the effective radiation dose. Methods: Initial brain PET measurements were performed at baseline and after oral administration of 5 mg/kg of LY2886721, a BACE1 inhibitor, in 2 cynomolgus monkeys. Kinetic analysis was performed with the radiometabolite-corrected plasma input function. In addition, a wide dose range of another BACE1 inhibitor, PF-06663195, was examined to investigate the relationship between the brain target occupancy and plasma concentration of the drug. Finally, the effective radiation dose of 18 F-PF-06684511 was estimated on the basis of the whole-body PET measurements in NHPs. Results: Radiolabeling was accomplished successfully with an incorporation radiochemical yield of 4%-12% (decay-corrected) from 18 F ion. The radiochemical purity was greater than 99%. The whole-brain uptake of 18 F-PF-06684511 peaked (∼220% SUV) at approximately 20 min and decreased thereafter (∼100% SUV at 180 min). A 2-tissue-compartment model described the time-activity curves well. Pretreatment with LY2886721 reduced the total distribution volume of 18 F-PF-06684511 by 48%-80% depending on the brain region, confirming its in vivo specificity. BACE1 occupancy of PF-06663195, estimated using the Lassen occupancy plot, showed a dose-dependent increase. The effective dose of 18 F-PF-06684511 was 0.043 mSv/ MBq for humans. Conclusion: 18 F-PF-06684511 is the first successful PET radioligand for BACE1 brain imaging that demonstrates favorable in vivo binding and brain kinetics in NHPs.

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Quantitative Analysis of ¹⁸F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

et al. 2018

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“…Although still at an initial stage, innovative molecular imaging for BACE1 assessment is under development. In line with the high-affinity of BACE1 inhibitors, recent efforts to develop brain-penetrant PET radiotracers, such as the highly potent selective aminothiazine inhibitor, PF-06684511 have been made [ 70 ].…”

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confidence: 99%

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

Vanmechelen¹,

Zetterberg

Galgani

et al. 2020

Alz Res Therapy

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β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer’s disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction. In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction. The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results. BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.

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“…[ 18 F]PF-06684511 was synthesized as reported previously [4,5]. In brief, an aqueous [ 18 F]fluoride was produced via the 18 O(p,n) 18 F nuclear reaction using a GE Medical Systems PETtrace cyclotron in a silver fluoride-18 water target.…”

Section: Radioligand Synthesismentioning

confidence: 99%

“…The PET radioligand [ 18 F]PF-06684511 has been developed for in vivo imaging and quantification of BACE1 [4]. Recently, we showed that [ 18 F]PF-06684511 displays suitable kinetic properties in the brain of non-human primates (NHPs) and also reported a dose-dependent blocking effect on [ 18 F]PF-06684511 brain uptake by BACE1 inhibitors [5].…”

Section: Introductionmentioning

confidence: 99%

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511

Arakawa

Takano

Stenkrona

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose Beta-secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer's disease. [ 18 F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [ 18 F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [ 18 F]PF-06684511 in healthy volunteers. Methods Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (V T ) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of V T were calculated as reliability measures. Results In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. V T (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRVand ICC of V T (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). Conclusion The ED of [ 18 F]PF-06684511 was similar to other 18 F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of V T was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [ 18 F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain.

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Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain

Cited by 17 publications

References 32 publications

Quantitative Analysis of ¹⁸F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

Quantitative Analysis of ¹⁸F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511

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Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain

Cited by 17 publications

References 32 publications

Quantitative Analysis of 18F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

Quantitative Analysis of 18F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

β-Secretase1 biological markers for Alzheimer’s disease: state-of-art of validation and qualification

PET imaging of beta-secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [18F]PF-06684511

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Quantitative Analysis of ¹⁸F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain

Quantitative Analysis of ¹⁸F-PF-06684511, a Novel PET Radioligand for Selective β-Secretase 1 Imaging, in Nonhuman Primate Brain