Kinetic isotope effects and synthetic strategies for deuterated carbon-11 and fluorine-18 labelled PET radiopharmaceuticals

Klenner, Mitchell A.; Pascali, Giancarlo; Fraser, Benjamin H.; Darwish, Tamim A.

doi:10.1016/j.nucmedbio.2021.03.011

Cited by 12 publications

(15 citation statements)

References 312 publications

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“…As shown in Figure , 23% of the activity in plasma corresponds to intact [ 18 F]LU13 , while the remaining activity consists of only more polar radiometabolites. Confirming our working hypothesis to increase the metabolic stability by introducing a deuterated 4-fluorobutyl chain in [ 18 F]LU13 , , a smaller fraction of radiometabolites has been detected for [ 18 F]LU13 compared with the structurally analogue [ 18 F]5 at this time-point (fraction of polar metabolites <5 versus 10%, respectively).…”

Section: Results and Discussionsupporting

confidence: 72%

“…50 Alternatively, the deuteration of fluoroalkyl residues was shown to considerably improve the metabolic stability for a number of PET radioligands. 51 In our efforts to increase the binding affinity of our ligands, we also investigated the influence of the C-6 substitution. The most promising candidate was selected for 18 Flabeling and biological evaluation.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The modifications performed at the N -alkyl chain are responsible for the improved metabolic stability, thus the introduction of the metabolically more stable fluoroaryl subunits is favored . Alternatively, the deuteration of fluoroalkyl residues was shown to considerably improve the metabolic stability for a number of PET radioligands . In our efforts to increase the binding affinity of our ligands, we also investigated the influence of the C -6 substitution.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

et al. 2022

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The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RK i = 0.6 nM; CB1RK i/CB2RK i > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [ 18 F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [ 18 F]LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [ 18 F]LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.

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Section: Results and Discussionsupporting

confidence: 72%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

et al. 2022

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“…Kuebler et al tested both [ 11 C]MODAG-001 and the deuterium incorporated (d 3 )-[ 11 C]MODAG-001 [12]; deuterium incorporation was meant to improve the pharmacokinetic and metabolic pro le of the radioligand [32]. Notably, we observed faster metabolism in the pigs than what was observed in the mice, which are much smaller mammals [33].…”

Section: Discussionmentioning

confidence: 65%

Evaluation of the α-synuclein PET Radiotracer (d3)-[11C]MODAG-001 in Pigs

Raval

Madsen

Shalgunov

et al. 2022

Preprint

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Background:A positron emission tomography (PET) radiotracer to neuroimage α-synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinson's disease, where elevated aggregate levels is a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of α-synuclein pre-formed fibrils (α-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 µg α-PFF, and in the other hemisphere, either 75 µg α-PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimer’s disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region.Results:The α-PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 µg α-PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 µg and 75 µg injected region of α-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. Conclusion:We find that both α-PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral α-synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

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“…]MODAG-001 and the deuterium incorporated (d 3 )-[ 11 C]MODAG-001 [12]; deuterium incorporation was meant to improve the pharmacokinetic and metabolic profile of the radioligand [32]. Notably, we observed faster metabolism in the pigs than what was observed in the mice, which are much smaller mammals [33].…”

Section: Kuebler Et Al Tested Both [ 11 Cmentioning

confidence: 80%

Evaluation of the α-synuclein PET radiotracer (d₃)-[¹¹C]MODAG-001 in pigs

Raval

Madsen

Shalgunov

et al. 2022

Preprint

View full text Add to dashboard Cite

Background: A positron emission tomography (PET) radiotracer to neuroimage α-synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinson's disease, where elevated aggregate levels is a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of α-synuclein pre-formed fibrils (α-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 μg α-PFF, and in the other hemisphere, either 75 μg α-PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimer's disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region. Results: The α-PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 μg α-PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 μg and 75 μg injected region of α-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. Conclusion: We find that both α-PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral α-synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

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Kinetic isotope effects and synthetic strategies for deuterated carbon-11 and fluorine-18 labelled PET radiopharmaceuticals

Cited by 12 publications

References 312 publications

Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Evaluation of the α-synuclein PET Radiotracer (d3)-[11C]MODAG-001 in Pigs

Evaluation of the α-synuclein PET radiotracer (d₃)-[¹¹C]MODAG-001 in pigs

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Kinetic isotope effects and synthetic strategies for deuterated carbon-11 and fluorine-18 labelled PET radiopharmaceuticals

Cited by 12 publications

References 312 publications

Structure-Based Design, Optimization, and Development of [18F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Structure-Based Design, Optimization, and Development of [18F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Evaluation of the α-synuclein PET Radiotracer (d3)-[11C]MODAG-001 in Pigs

Evaluation of the α-synuclein PET radiotracer (d3)-[11C]MODAG-001 in pigs

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Product

Resources

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Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Structure-Based Design, Optimization, and Development of [¹⁸F]LU13: A Novel Radioligand for Cannabinoid Receptor Type 2 Imaging in the Brain with PET

Evaluation of the α-synuclein PET radiotracer (d₃)-[¹¹C]MODAG-001 in pigs