Synthesis and evaluation of a (18)F-curcumin derivate for β-amyloid plaque imaging.
BACKGROUND
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 (18)F-labeled curcumin derivate ([(18)F]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 [(18)F]4 using nucleophilic (18)F-fluorination and click chemistry. Binding of [(18)F]4 to β-amyloid plaques in the transgenic APP23 mouse brain cryosections was studied in vitro using heterologous competitive binding against PIB. [(18)F]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 [(18)F]4 was 21 ± 11%, the specific activity exceeded 1TBq/μmol, and the radiochemical purity exceeded 99.3% at the end of synthesis. In vitro studies of [(18)F]4 with the transgenic APP23 mouse revealed high β-amyloid plaque binding. In vivo and ex vivo studies demonstrated that [(18)F]4 has fast clearance from the blood, moderate metabolism but low blood-brain barrier (BBB) penetration.


CONCLUSIONS
[(18)F]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, [(18)F]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.
Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku, Porthaninkatu 3, FI-20500 Turku, Finland.
Johanna
J
Rokka
Turku PET Centre, Preclinical Imaging, University of Turku, Tykistökatu 6, FI-20520 Turku, Finland.
Anniina
A
Snellman
Department of Biotechnology and Bioscience, University of Milano-Bicocca, I-20126 Milano, Italy.
Cristiano
C
Zona
Department of Biotechnology and Bioscience, University of Milano-Bicocca, I-20126 Milano, Italy.
Barbara
B
La Ferla
Department of Biotechnology and Bioscience, University of Milano-Bicocca, I-20126 Milano, Italy.
Francesco
F
Nicotra
Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche 'Mario Negri', I-20156 Milano, Italy.
Mario
M
Salmona
Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche 'Mario Negri', I-20156 Milano, Italy.
Gianluigi
G
Forloni
Turku PET Centre, Preclinical Imaging, University of Turku, Tykistökatu 6, FI-20520 Turku, Finland.
Merja
M
Haaparanta-Solin
Turku PET Centre c/o Turku University Hospital, University of Turku, PO Box 52, FI-20521 Turku, Finland.
Juha O
JO
Rinne
Turku PET Centre, Radiopharmaceutical Chemistry Laboratory, University of Turku, Porthaninkatu 3, FI-20500 Turku, Finland; Turku PET Centre, Accelerator Laboratory, Åbo Akademi University, Porthansgatan 3, FI-20500 Turku, Finland. Electronic address: olof.solin@utu.fi.
Olof
O
Solin
D000544:Alzheimer Disease / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D003474:Curcumin / Q000737:chemistry* / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D003474:Curcumin
Alzheimer’s disease; Click chemistry; Curcumin; Nucleophilic (18)F-fluorination; Positron emission tomography (PET); β-Amyloid