Evaluation of 5-[18F]fluoropropylepidepride as a potential PET radioligand for imaging dopamine D2 receptors.
This study evaluated the utility of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2,3 - dimethoxybenzamide ([18F]fluorpropylepidepride), [18F]5-FPrEpid, as a ligand for PET studies of cerebral dopamine D2 receptors. The in vitro affinity for the rat striatal dopamine D2 receptor, KD 138 pM, was determined by Scatchard analysis of in vitro binding to rat striatal homogenate. The apparent lipophilicity, log kw 1.6, was measured with reverse phase HPLC at pH 7.5. The receptor specificity was determined by competitive displacement of [18F]5-FPrEpid by a variety of neurotransmitter ligands. Only dopamine D2 ligands displaced [18F]5-FPrEpid with high affinity. Positron tomographic imaging studies in primates of [18F]5-FPrEpid demonstrated a stable striatal uptake of 0.02% injected dose/ml for up to 5 h after injection. The striatal: cerebellar ratio increased from 2 at 15 min, to 7 at 200 min, and to 10 at 300 min. Striatal uptake was displaceable by haloperidol (1 mg/kg) or raclopride (2.5 mg/kg) to cerebellar levels with a t1/2 of washout of 9 or 15 min. Striatal uptake was mildly susceptible to displacement by d-amphetamine (1-2 mg/kg) released endogenous dopamine; d-amphetamine administration produced a 10% h increase in the rate of striatal washout. Although uptake in the striatum is reversible, an equilibrium between receptor bound [18F]5-FPrEpid in striatum and [18F]5-FPrEpid in plasma is not reached within 5 h postinjection.
Kessler
R M
RM
Department of Radiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Votaw
J R
JR
de Paulis
T
T
Bingham
D R
DR
Ansari
M S
MS
Mason
N S
NS
Holburn
G
G
Schmidt
D E
DE
Votaw
D B
DB
Manning
R G
RG
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000032:analysis* / Q000378:metabolism; D014055:Tomography, Emission-Computed / Q000379:methods*
D001549:Benzamides; D005462:Fluorine Radioisotopes; D007457:Iodine Radioisotopes; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; C063525:epidepride; C085179:5-fluoropropylepidepride