Synthesis and evaluation of a 18F-curcumin derivate for β-amyloid plaque imaging

Johanna Rokka, Anniina Snellman, Cristiano Zona, Barbara La Ferla, Francesco Nicotra, Mario Salmona, Gianluigi Forloni, Merja Haaparanta-Solin, Juha O. Rinne, Olof Solin

Research output: Contribution to journalArticle

Abstract

Introduction Curcumin is a neuroprotective compound that inhibits the formation of amyloid oligomers and fibrils and binds to β-amyloid plaques in Alzheimer's disease (AD). We aimed to synthesize an 18F-labeled curcumin derivate ([18F]4) and to characterize its positron emission tomography (PET) tracer-binding properties to β-amyloid plaques in a transgenic APP23 mouse model of AD. Methods We utilized facile one-pot synthesis of [18F]4 using nucleophilic 18F-fluorination and click chemistry. Binding of [18F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [18F]4 uptake was studied ex vivo in rodents and in vivo using PET/computed tomography of transgenic APP23 and wild-type control mice. Results The radiochemical yield of [18F]4 was 21 ± 11%, the specific activity exceeded 1 TBq/μmol, and the radiochemical purity exceeded 99.3% at the end of synthesis. In vitro studies of [18F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [18F]4 has fast clearance from the blood, moderate metabolism but low blood-brain barrier (BBB) penetration. Conclusions [ 18F]4 was synthesized in high yield and excellent quality. In vitro studies, metabolite profile, and fast clearance from the blood indicated a promising tracer for Aβ imaging. However, [18F]4 has low in vivo BBB penetration and thus further studies are needed to reveal the reason for this and to possibly overcome this issue.

Original languageEnglish
Pages (from-to)2753-2762
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number9
DOIs
Publication statusPublished - May 1 2014

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Curcumin
Amyloid Plaques
Amyloid
Transgenic Mice
Imaging techniques
Blood-Brain Barrier
Positron emission tomography
Alzheimer Disease
Click Chemistry
Blood
Competitive Binding
Halogenation
Fluorination
Positron-Emission Tomography
Rodentia
Metabolites
Oligomers
Metabolism
Tomography
Brain

Keywords

  • Alzheimer's disease
  • Click chemistry
  • Curcumin
  • Positron emission tomography (PET)
  • β-Amyloid

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Synthesis and evaluation of a 18F-curcumin derivate for β-amyloid plaque imaging. / Rokka, Johanna; Snellman, Anniina; Zona, Cristiano; La Ferla, Barbara; Nicotra, Francesco; Salmona, Mario; Forloni, Gianluigi; Haaparanta-Solin, Merja; Rinne, Juha O.; Solin, Olof.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 9, 01.05.2014, p. 2753-2762.

Research output: Contribution to journalArticle

Rokka, J, Snellman, A, Zona, C, La Ferla, B, Nicotra, F, Salmona, M, Forloni, G, Haaparanta-Solin, M, Rinne, JO & Solin, O 2014, 'Synthesis and evaluation of a 18F-curcumin derivate for β-amyloid plaque imaging', Bioorganic and Medicinal Chemistry, vol. 22, no. 9, pp. 2753-2762. https://doi.org/10.1016/j.bmc.2014.03.010
Rokka, Johanna ; Snellman, Anniina ; Zona, Cristiano ; La Ferla, Barbara ; Nicotra, Francesco ; Salmona, Mario ; Forloni, Gianluigi ; Haaparanta-Solin, Merja ; Rinne, Juha O. ; Solin, Olof. / Synthesis and evaluation of a 18F-curcumin derivate for β-amyloid plaque imaging. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 9. pp. 2753-2762.
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abstract = "Introduction Curcumin is a neuroprotective compound that inhibits the formation of amyloid oligomers and fibrils and binds to β-amyloid plaques in Alzheimer's disease (AD). We aimed to synthesize an 18F-labeled curcumin derivate ([18F]4) and to characterize its positron emission tomography (PET) tracer-binding properties to β-amyloid plaques in a transgenic APP23 mouse model of AD. Methods We utilized facile one-pot synthesis of [18F]4 using nucleophilic 18F-fluorination and click chemistry. Binding of [18F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [18F]4 uptake was studied ex vivo in rodents and in vivo using PET/computed tomography of transgenic APP23 and wild-type control mice. Results The radiochemical yield of [18F]4 was 21 ± 11{\%}, the specific activity exceeded 1 TBq/μmol, and the radiochemical purity exceeded 99.3{\%} at the end of synthesis. In vitro studies of [18F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [18F]4 has fast clearance from the blood, moderate metabolism but low blood-brain barrier (BBB) penetration. Conclusions [ 18F]4 was synthesized in high yield and excellent quality. In vitro studies, metabolite profile, and fast clearance from the blood indicated a promising tracer for Aβ imaging. However, [18F]4 has low in vivo BBB penetration and thus further studies are needed to reveal the reason for this and to possibly overcome this issue.",
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AU - Rokka, Johanna

AU - Snellman, Anniina

AU - Zona, Cristiano

AU - La Ferla, Barbara

AU - Nicotra, Francesco

AU - Salmona, Mario

AU - Forloni, Gianluigi

AU - Haaparanta-Solin, Merja

AU - Rinne, Juha O.

AU - Solin, Olof

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N2 - Introduction Curcumin is a neuroprotective compound that inhibits the formation of amyloid oligomers and fibrils and binds to β-amyloid plaques in Alzheimer's disease (AD). We aimed to synthesize an 18F-labeled curcumin derivate ([18F]4) and to characterize its positron emission tomography (PET) tracer-binding properties to β-amyloid plaques in a transgenic APP23 mouse model of AD. Methods We utilized facile one-pot synthesis of [18F]4 using nucleophilic 18F-fluorination and click chemistry. Binding of [18F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [18F]4 uptake was studied ex vivo in rodents and in vivo using PET/computed tomography of transgenic APP23 and wild-type control mice. Results The radiochemical yield of [18F]4 was 21 ± 11%, the specific activity exceeded 1 TBq/μmol, and the radiochemical purity exceeded 99.3% at the end of synthesis. In vitro studies of [18F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [18F]4 has fast clearance from the blood, moderate metabolism but low blood-brain barrier (BBB) penetration. Conclusions [ 18F]4 was synthesized in high yield and excellent quality. In vitro studies, metabolite profile, and fast clearance from the blood indicated a promising tracer for Aβ imaging. However, [18F]4 has low in vivo BBB penetration and thus further studies are needed to reveal the reason for this and to possibly overcome this issue.

AB - Introduction Curcumin is a neuroprotective compound that inhibits the formation of amyloid oligomers and fibrils and binds to β-amyloid plaques in Alzheimer's disease (AD). We aimed to synthesize an 18F-labeled curcumin derivate ([18F]4) and to characterize its positron emission tomography (PET) tracer-binding properties to β-amyloid plaques in a transgenic APP23 mouse model of AD. Methods We utilized facile one-pot synthesis of [18F]4 using nucleophilic 18F-fluorination and click chemistry. Binding of [18F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [18F]4 uptake was studied ex vivo in rodents and in vivo using PET/computed tomography of transgenic APP23 and wild-type control mice. Results The radiochemical yield of [18F]4 was 21 ± 11%, the specific activity exceeded 1 TBq/μmol, and the radiochemical purity exceeded 99.3% at the end of synthesis. In vitro studies of [18F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [18F]4 has fast clearance from the blood, moderate metabolism but low blood-brain barrier (BBB) penetration. Conclusions [ 18F]4 was synthesized in high yield and excellent quality. In vitro studies, metabolite profile, and fast clearance from the blood indicated a promising tracer for Aβ imaging. However, [18F]4 has low in vivo BBB penetration and thus further studies are needed to reveal the reason for this and to possibly overcome this issue.

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KW - β-Amyloid

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