Novel electrophilic synthesis of 6-[¹⁸F]fluorodopamine and comprehensive biological evaluation.
OBJECTIVE
6-[(18)F]Fluorodopamine (4-(2-aminoethyl)-5-[(18)F]fluorobenzene-1,2-diol, 6-[(18)F]FDA) is a tracer for imaging sympathetically innervated tissues. Previous electrophilic labelling methods produced 6-[(18)F]FDA with low specific radioactivity (SA) which has limited its wider use. Our aim was to employ electrophilic labelling and increase the SA to around 15 GBq/μmol. We also sought to determine an extensive biodistribution pattern for 6-[(18)F]FDA in rats in order to thoroughly identify tissues with dense sympathetic innervation that were specifically labelled with 6-[(18)F]FDA. In addition, to investigate the safety profile of 6-[(18)F]FDA in larger animals, we performed in vivo studies in pigs.


METHODS
6-[(18)F]FDA was synthesised using high SA electrophilic [(18)F]F(2) as the labelling reagent. Biodistribution and metabolism of 6-[(18)F]FDA was determined ex vivo in rats, and in vivo studies were done in pigs.


RESULTS
6-[(18)F]FDA was synthesised with 2.6 ± 1.1% radiochemical yield. The total amount of purified 6-[(18)F]FDA was 663 ± 291 MBq at the end of synthesis (EOS). SA, decay corrected to EOS, was 13.2 ± 2.7 GBq/μmol. Radiochemical purity exceeded 99.0%. Specific uptake of 6-[(18)F]FDA was demonstrated in heart, lung, pancreas, adrenal gland, lower large intestine (LLI), eye, thyroid gland, spleen and stomach tissue. 6-[(18)F]FDA in rat plasma declined rapidly, with a half-life of 2 min, indicating fast metabolism. In vivo PET studies in pigs confirmed the tracer could be used safely without pharmacological effects.


CONCLUSIONS
6-[(18)F]FDA was synthesised with good radiopharmaceutical quality and yields high enough for several human PET studies. The SA of 6-[(18)F]FDA was improved by 50- to 500-fold compared to previous electrophilic methods. Uptake of 6-[(18)F]FDA was specific in various peripheral organs, indicating that 6-[(18)F]FDA PET can be used to investigate sympathoneural functions beyond cardiac studies when higher specific uptake is achieved.
Turku PET Centre, University of Turku, Radiopharmaceutical Chemistry Laboratory, Kiinamyllynkatu 4-8, 20520, Turku, Finland. olesko@utu.fi
Olli
O
Eskola
Tove J
TJ
Grönroos
Alexandru
A
Naum
Päivi
P
Marjamäki
Sarita
S
Forsback
Jörgen
J
Bergman
Sami
S
Länkimäki
Jan
J
Kiss
Timo
T
Savunen
Juhani
J
Knuuti
Merja
M
Haaparanta
Olof
O
Solin
D000818:Animals; D001692:Biological Transport; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D004298:Dopamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D051381:Rats; D013552:Swine
C029253:6-fluorodopamine; D004298:Dopamine