A series of 18F-labelled pyridinylphenyl amides as subtype-selective radioligands for the dopamine D3 receptor.
Synthesis, biological activity, and structure-selectivity relationship (SSR) studies of a novel series of potential dopamine D3 receptor radioligands as imaging agents for positron emission tomography (PET) are reported. Considering a structurally diverse library of D3 ligands, SSR studies were performed for a new series of fluorinated pyridinylphenyl amides using CoMFA and CoMSIA methods. The in vitro D3 affinities of the predicted series of biphenyl amide ligands 9 a-d revealed single-digit to sub-nanomolar potencies (K(i)=0.52-1.6 nM), displaying excellent D3 selectivity over the D2 subtype of 110- to 210-fold for the test compounds 9 a-c. Radiofluorination by nucleophilic substitution of Br or NO(2) by (18)F led to radiochemical yields of 66-92 % for [(18)F]9 a-d. However, the specific activities of [(18)F]9 b and [(18)F]9 d were insufficient, rendering their use for in vivo studies impossible. Biodistribution studies of [(18)F]9 a and [(18)F]9 c using rat brain autoradiography revealed accumulation in the ventricles, thus indicating insufficient biokinetic properties of [(18)F]9 a and [(18)F]9 c for D3 receptor imaging in vivo.
Hocke
Carsten
C
Friedrich Alexander University Erlangen-Nürnberg, Clinic of Nuclear Medicine, Friedrich Alexander University, Krankenhausstrasse 12, 91054 Erlangen, Germany. carsten.hocke@uk-erlangen.de
Maschauer
Simone
S
Hübner
Harald
H
Löber
Stefan
S
Utz
Wolfgang
W
Kuwert
Torsten
T
Gmeiner
Peter
P
Prante
Olaf
O
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D049268:Positron-Emission Tomography; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D005462:Fluorine Radioisotopes; D008024:Ligands; D020033:Protein Isoforms; D050637:Receptors, Dopamine D3