Synthesis and evaluation of fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives for dopamine D4 receptor imaging.
Seven fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were synthesized based on a lead ligand, 3-[[4-(4-iodophenyl)piperazin-1-yl]-methyl]-1H-pyrrolo[2,3-b]pyridine (L-750,667) and evaluated as potential dopamine D(4) receptor imaging agents by positron emission tomography (PET). Binding affinities of these ligands for the dopamine D(2), D(3), and D(4) receptor subtypes were measured in vitro. Most ligands showed high and selective binding for the D(4) receptor. Ligand 7 had high affinity for the D(4) receptor, whereas ligands 1, 2, and 6 showed high selectivity for the D(4) receptor. LogP values were calculated for the ligands in this series and ligand 6 had the lowest lipophilicity. (18)F-labeled ligand 7 demonstrated a uniform regional brain distribution and a rapid washout in mice, probably due to nonspecific binding. Based on their in vitro binding properties and calculated logP values, ligand 6 appears to have the most promise for dopamine D(4) receptor imaging.
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, South Korea.
Seung-Jun
SJ
Oh
Kyo Chul
KC
Lee
Sang-Yoon
SY
Lee
Eun Kyoung
EK
Ryu
Hideo
H
Saji
Yearn Seong
YS
Choe
Dae Yoon
DY
Chi
Sang Eun
SE
Kim
Jeewoo
J
Lee
Byung-Tae
BT
Kim
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005461:Fluorine / Q000737:chemistry / Q000378:metabolism*; D006859:Hydrogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4
C493600:Drd4 protein, mouse; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D005461:Fluorine; D006859:Hydrogen