Evaluation of 18F-FA-4 and 11C-pipzA-4 as radioligands for the in vivo evaluation of the high-affinity choline uptake system.
4,4'-Bis-1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl-biphenyl (A-4), a tertiary amine analog of hemicholinium-3 (HC-3), is an inhibitor of the sodium-dependent high-affinity choline uptake (HACU) system. We have evaluated 4-[1-hydroxy-2-(4-(18)F-fluoromethylpiperidin-1-yl)ethyl]-4'-[1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl]biphenyl ((18)F-FA-4) and 4-[1-hydroxy-2-(4-(11)C-methylpiperazin-1-yl)ethyl]-4'-[1-hydroxy-2-(4-methylpiperidin-1-yl)ethyl]biphenyl ((11)C-pipzA-4), an (18)F- and a (11)C-labeled derivative of A-4 as potential in vivo tracers for the HACU system.


METHODS
The biodistribution of both compounds was determined in mice, and the intracerebral distribution was visualized by ex vivo and in vitro autoradiography. The in vitro affinity of the compounds was determined by a displacement study with (3)H-HC-3 on mice brain slices.


RESULTS
In mice, both tracers show a high and persistent brain uptake. In vitro autoradiography shows binding to the striatum, whereas ex vivo autoradiography shows homogeneous binding throughout the brain. FA-4 and pipzA-4 inhibited the (3)H-HC-3 binding with a 50% inhibitory concentration of 57 nmol/L and 320 nmol/L, respectively.


CONCLUSIONS
The evaluated compounds have affinity for HACU and show high uptake in the brain. In vitro binding of the compounds to the striatum cannot be inhibited by the presence of HC-3, whereas binding of HC-3 was inhibited by the presence of both FA-4 and pipzA-4, suggesting allosteric binding.
Gilissen
Christa
C
Laboratory of Radiopharmaceutical Chemistry, Faculteit Farmaceutische Wetenschappen, Katholieke Universiteit Leuven, Leuven, Belgium.
de Groot
Tjibbe J
TJ
Bronfman
Francesca
F
van Leuven
Fred
F
Verbruggen
Alfons M
AM
Bormans
Guy M
GM
D000818:Animals; D001345:Autoradiography; D001713:Biphenyl Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002531:Cerebellum / Q000378:metabolism; D003337:Corpus Callosum / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D003903:Deuterium / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006426:Hemicholinium 3 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011869:Radioligand Assay / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013687:Telencephalon / Q000378:metabolism; D014018:Tissue Distribution
D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D026901:Membrane Transport Proteins; D010880:Piperidines; D019275:Radiopharmaceuticals; C065637:choline transporter; D006426:Hemicholinium 3; C001771:4,4'-(2-(4-methylpiperidyl)-1-hydroxyethyl)biphenyl; D003903:Deuterium