2-(2'-((Dimethylamino)methyl)-4'-(3-[(18)F]fluoropropoxy)-phenylthio)benzenamine for positron emission tomography imaging of serotonin transporters.
BACKGROUND
A new (18)F ligand, 2-(2'-((dimethylamino)methyl)-4'-(3-[(18)F]fluoropropoxy)-phenylthio)benzenamine ([(18)F]1), for positron emission tomography (PET) imaging of serotonin transporters (SERT) was evaluated.


METHODS
Binding affinity was determined through in vitro binding assays with LLC-PK1 cells overexpressing SERT, NET or DAT (LLC-SERT, LLC-NET and LLC-DAT) and with rat cortical homogenates. Localization and selectivity of [(18)F]1 binding in vivo were evaluated by biodistribution, autoradiography and A-PET imaging studies in rats.


RESULTS
This compound displayed excellent binding affinity for SERT in vitro with K(i)=0.33 and 0.24 nM in LLC-SERT and rat cortical homogenates, respectively. Biodistribution studies with [(18)F]1 showed good brain uptake (1.61% dose/g at 2 min postinjection), high uptake into the hypothalamus (1.22% dose/g at 30 min) and a high target-to-nontarget (hypothalamus to cerebellum) ratio of 9.66 at 180 min postinjection. Pretreatment with a SERT selective inhibitor considerably inhibited [(18)F]1 binding in biodistribution studies. Ex vivo autoradiography reveals [(18)F]1 localization to brain regions with high SERT density, and this binding was blocked by pretreatment with SERT selective inhibitors. Small animal PET (A-PET) imaging in rats provided clear images of tracer localization in the thalamus, midbrain and striatum. In A-PET chasing experiments, injecting a SERT selective inhibitor 75 min post-tracer injection causes a dramatic reduction in regional radioactivity and the target-to-nontarget ratio.


CONCLUSIONS
The results of the biological studies and the ease of radiosynthesis with moderately good radiochemical yield (RCY=10-35%) make [(18)F]1 an excellent candidate for SERT PET imaging.
Wang
Julie L
JL
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Parhi
Ajit K
AK
Oya
Shunichi
S
Lieberman
Brian
B
Kung
Mei-Ping
MP
Kung
Hank F
HF
D000814:Aniline Compounds / Q000493:pharmacokinetics*; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D018374:LLC-PK1 Cells; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000032:analysis / Q000737:chemistry* / Q000187:drug effects; D014018:Tissue Distribution
C527727:2-(2-((dimethylamino)methyl)-4-(3-fluoropropoxy)phenylthio)benzenamine; D000814:Aniline Compounds; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins