Synthesis and preliminary evaluation of [18F]-labeled 2-oxoquinoline derivatives for PET imaging of cannabinoid CB2 receptor.
BACKGROUND
The cannabinoid receptor type 2 (CB(2)) is an important target for development of drugs and imaging agents for diseases, such as neuroinflammation, neurodegeneration and cancer. Recently, we reported synthesis and results of in vitro receptor binding of a focused library of fluorinated 2-oxoquinoline derivatives as CB(2) receptor ligands. Some of the compounds demonstrated to be good CB(2)-specific ligands with Ki values in the nanomolar to subnanomolar concentrations; therefore, we pursued the development of their (18)F-labeled analogues that should be useful for positron emission tomography (PET) imaging of CB(2) receptor expression. Here, we report the radiosynthesis of two (18)F-labeled 2-oxoquinoline derivatives and the preliminary in vitro and ex vivo evaluation of one compound as a CB(2)-specific radioligand.


METHODS
4-[(18)F]fluorobenzyl amine [(18)F]-3 was prepared by radiofluorination of 4-cyano-N,N,N-trimethylanilinium triflate salt followed by reduction with LiAlH(4) and then coupled with acid chlorides 11 and 12 to afford [(18)F]-13 and [(18)F]-14. In vitro CB(2) receptor binding assay was performed using U87 cells transduced with CB(2) and CB(1) receptor. Ex vivo autoradiography was performed with [(18)F]-14 on spleen and on CB(2)- and CB(1)-expressing and wild-type U87 subcutaneous tumors grown in mice.


RESULTS
The radiochemical yields of [(18)F]-13 and [(18)F]-14 were 10%-15.0% with an average of 12% (n=10); radiochemical purity was >99% with specific activity 1200 mCi/μmol. The dissociation constant Kd for [(18)F]-14 was 3.4 nM. Ex vivo autoradiography showed accumulation of [(18)F]-14 in the CB(2)-expressing tumor.


CONCLUSIONS
Two new [(18)F]-labeled CB(2) ligands have been synthesized. Compound [(18)F]-14 appears to be a potential PET imaging agent for the assessment of CB(2) receptor expression; however, poor solubility restrain its use in vivo.
Nashaat
N
Turkman
Aleksander
A
Shavrin
Vincenzo
V
Paolillo
Hsin Hsien
HH
Yeh
Leo
L
Flores
Suren
S
Soghomonian
Brian
B
Rabinovich
Andrei
A
Volgin
Juri
J
Gelovani
Mian
M
Alauddin
D000818:Animals; D001345:Autoradiography; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D060326:Chemistry Techniques, Synthetic; D005462:Fluorine Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011854:Radiochemistry; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*
D005462:Fluorine Radioisotopes; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2