Pharmacokinetics of [¹⁸F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer's disease.
OBJECTIVE
The aim of this study was to investigate the potential of [(18)F]flutemetamol as a preclinical PET tracer for imaging β-amyloid (Aβ) deposition by comparing its pharmacokinetics to those of [(11)C]Pittsburgh compound B ([(11)C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [(18)F]flutemetamol to Aβ deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease.


METHODS
[(18)F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [(11)C]PIB and [(18)F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [(18)F]flutemetamol to Aβ deposits was also studied using ex vivo and in vitro autoradiography. The location of Aβ deposits in the brain was determined with thioflavine S staining and immunohistochemistry.


RESULTS
The pharmacokinetics of [(18)F]flutemetamol resembled that of [(11)C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [(18)F]flutemetamol into radioactive metabolites was faster than that of [(11)C]PIB. [(18)F]Flutemetamol cleared more slowly from the brain than [(11)C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [(11)C]PIB and [(18)F]flutemetamol were 2.28 and 6.65 μSv/MBq, respectively. Autoradiographs showed [(18)F]flutemetamol binding to fibrillar Aβ deposits in the brain of Tg2576 mice.


CONCLUSIONS
Based on its pharmacokinetic profile, [(18)F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging.
MediCity/PET Preclinical Laboratory, Turku PET Centre, University of Turku, Tykistökatu 6A, FI-20520 Turku, Finland.
Anniina
A
Snellman
Johanna
J
Rokka
Francisco R
FR
Lopez-Picon
Olli
O
Eskola
Ian
I
Wilson
Gill
G
Farrar
Mika
M
Scheinin
Olof
O
Solin
Juha O
JO
Rinne
Merja
M
Haaparanta-Solin
D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds / Q000493:pharmacokinetics*; D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics; D014018:Tissue Distribution
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D013844:Thiazoles; C581552:flutemetamol