In-vivo imaging characteristics of two fluorinated flumazenil radiotracers in the rat.
OBJECTIVE
[(11)C]Flumazenil shows promise as a clinical and research PET radiotracer to image changes in GABA(A) central benzodiazepine receptor (cBZR), but its widespread use has been limited by practical limitations of [(11)C]. This study evaluated the imaging characteristics of two fluorinated PET radiotracers in rats in vivo: [(18)F]fluoroflumazenil ([(18)F]FFMZ) and [(18)F]flumazenil ([(18)F]FMZ).


METHODS
PET acquisitions were performed on a small-animal scanner following injection of [(18)F]FFMZ in nine rats and [(18)F]FMZ in eight rats. The following treatments were investigated: (1) injection of the tracer dose, (2) presaturation then injection of the tracer dose, and (3) injection of the tracer dose followed by a displacement injection. Unchanged tracer was measured in plasma and brain structures in four animals 10 and 30 min after injection, and ex-vivo autoradiography was also performed.


RESULTS
For both [(18)F]FFMZ and [(18)F]FMZ maximal brain activity peaked rapidly, and was highest in the hippocampus (1.12+/-0.06 SUV, 1.24+/-0.10 SUV, respectively), and lowest in the pons (1.00+/-0.07 SUV, 1.03+/-0.09 SUV, respectively). By 50 min after injection, maximal uptake for [(18)F]FFMZ and [(18)F]FMZ had decreased in the hippocampus to 18+/-3% and 80+/-1% (p<0.01), respectively. The presaturation and displacement studies showed a higher nonspecific component for [(18)F]FFMZ than for [(18)F]FMZ. Metabolite studies showed that at 30 min only 10% of the signal was from [(18)F]FFMZ in the brain. This nonspecific binding was apparent on autoradiography. In contrast, [(18)F]FMZ accounted for >70% of the signal in the brain, which resulted in well-defined regional binding on autoradiography.


CONCLUSIONS
These results demonstrate that [(18)F]FMZ is a superior radiotracer to [(18)F]FFMZ for in-vivo PET imaging of the GABA(A)/cBZR, having slower metabolism and leading to lower concentrations of metabolites in the brain that results in a substantially better signal-to-noise ratio.
Dedeurwaerdere
Stefanie
S
Department of Medicine (RMH), University of Melbourne, Royal Parade, Parkville, Victoria, Australia.
Gregoire
Marie-Claude
MC
Vivash
Lucy
L
Roselt
Peter
P
Binns
David
D
Fookes
Christopher
C
Greguric
Ivan
I
Pham
Tien
T
Loc'h
Christian
C
Katsifis
Andrew
A
Hicks
Rodney J
RJ
O'Brien
Terence J
TJ
Myers
Damian E
DE
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism; D005442:Flumazenil / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D008297:Male; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000032:analysis / Q000378:metabolism; D015203:Reproducibility of Results
C483765:2'-fluoroflumazenil; D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; D011963:Receptors, GABA-A; D005442:Flumazenil