Fluorine-18 Radiolabeling Strategies—Advantages and Disadvantages of Currently Applied Labeling Methods

Edem, Patricia E.; Stéen, E. Johanna L.; Kjær, Andreas; Herth, Matthias M.

doi:10.1016/b978-0-12-812958-6.00002-1

Cited by 13 publications

(16 citation statements)

References 234 publications

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“…The DABTAs were designed such that they could be easily labeled with [ 18 F]fluorine due to its ideal combination of a 110-min physical half-life (logistically enables transport to satellite PET scanning facilities) in comparison to [ 11 C]carbon, whose shorter half-life (∼20 min) limits its usage to centers with on-site cyclotron; a clean decay profile (97% positron emission and 3% electron capture); and a low positron energy (maximum 0.635 MeV), which results in fairly short positron range (maximum 2.4 mm in water) hence high-resolution PET images (∼1 mm) (Shah and Westwell, 2007;Ariza et al, 2015;Jacobson et al, 2015;Edem et al, 2019) and lower patient dose per positron emission (Bailey et al, 2005;van der Born et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils

Uzuegbunam

Paslawski

et al. 2022

Front. Aging Neurosci.

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The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer–protein interactions were employed to predict surface sites and structure–property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4′-(3-[18F]fluoro-4-methoxyphenyl)-2,2′-bithiazole [18F]d2, 6-(4′-(3-[18F]fluoro-4-methoxyphenyl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d4, 4-(benzo [d][1,3]dioxol-5-yl)-4′-(6-[18F]fluoropyridin-3-yl)-2,2′-bithiazole [18F]d6, and 6-(4′-(6-[18F]fluoropyridin-3-yl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d8 were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d2, d4, d6, and d8 showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([18F]d2 and [18F]d4) or typical SNAr reaction ([18F]d6 and [18F]d8) with moderate-to-high radiochemical yields (13% – 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [18F]d2 and [18F]d4 showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [18F]d6 and [18F]d8 showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [18F]d6 and [18F]d8 were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [18F]d8 seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.

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Section: Introductionmentioning

confidence: 99%

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils

Uzuegbunam

Paslawski

et al. 2022

Front. Aging Neurosci.

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“…Some compounds show organ targeting or enzyme specificity after the introduction of fluorine atoms to the chemical structure. Like in other compounds, it is observed that the introduction of fluorine opens opportunities for other imaging modalities such as PET imaging [ 34 ]. Many new cyanine dyes are also being conjugated to targeting ligands for improved specificity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Applications of Selected Fluorine-Containing Fluorophores

Casa

Henary

2021

Molecules

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The synthesis of fluorine-containing small molecules has had numerous benefits of improving the quality and efficiency of many applications of these compounds. For example, fluorine adds promising functionalities in various areas of imaging (MRI, PET, and NIR); gives cell-targeting properties; and has demonstrated improvements in cell permeability, solubility, and other pharmacologic properties. For these and other numerous reasons, fluorination of molecules has grown in popularity in various fields of chemistry. Many reports show the effects observed from increasing the number of fluorine atoms on a fluorophore scaffold. This report will cover the most significant applications and improvements that fluorine has contributed to in various dye scaffolds such as BODIPY, rhodamine, phthalocyanine, and cyanine in the recent decade.

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“…Positron emission tomography (PET) is a medical imaging technique that can noninvasively study molecular processes in the brain and body without imparting physiological effects due to the use of tracer amounts of radiopharmaceuticals [ 1 , 2 ]. The radiolabeled dopamine transporter ligand, [ 18 F]FE-PE2I, has over the past few years been shown to be a valuable tool for the study of patients with Parkinson′s disease [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Fully Automated GMP-Compliant Synthesis of [18F]FE-PE2I

et al. 2021

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In the struggle to understand and accurately diagnose Parkinson′s disease, radiopharmaceuticals and medical imaging techniques have played a major role. By being able to image and quantify the dopamine transporter density, noninvasive diagnostic imaging has become the gold standard. In the shift from the first generation of SPECT tracers, the fluorine-18-labeled tracer [18F]FE-PE2I has emerged as the agent of choice for many physicians. However, implementing suitable synthesis for the production of [18F]FE-PE2I has proved more challenging than expected. Through a thorough analysis of the relevant factors affecting the final radiochemical yield, we were able to implement high-yielding fully automated GMP-compliant synthesis of [18F]FE-PE2I on a Synthera®+ platform. By reaching RCYs up to 62%, it allowed us to isolate 25 GBq of the formulated product, and an optimized formulation resulted in the shelf life of 6 h, satisfying the increased demand for this radiopharmaceutical.

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Fluorine-18 Radiolabeling Strategies—Advantages and Disadvantages of Currently Applied Labeling Methods

Cited by 13 publications

References 234 publications

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils

Synthesis and Applications of Selected Fluorine-Containing Fluorophores

Fully Automated GMP-Compliant Synthesis of [18F]FE-PE2I

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