[18F]DPA-C5yne, a novel fluorine-18-labelled analogue of DPA-714: radiosynthesis and preliminary evaluation as a radiotracer for imaging neuroinflammation with PET.
DPA-C5yne, the lead compound of a novel series of DPA-714 derivatives in which the fluoroethoxy chain linked to the phenylpyrazolopyrimidine scaffold has been replaced by a fluoroalkyn-1-yl moiety, is a high affinity (Ki : 0.35 nM) and selective ligand targeting the translocator protein 18 kDa. In the present work, DPA-C5yne was labelled with no-carrier-added [(18)F]fluoride based on a one-step tosyloxy-for-fluorine nucleophilic substitution reaction, purified by cartridge and HPLC, and formulated as an i.v. injectable solution using a TRACERLab FX N Pro synthesizer. Typically, 4.3-5.2 GBq of [(18)F]DPA-C5yne, ready-to-use, chemically and radiochemically pure (> 95%), was obtained with specific radioactivities ranging from 55 to 110 GBq/µmol within 50-60 min, starting from a 30 GBq [(18)F]fluoride batch (14-17%). LogP and LogD of [(18)F]DPA-C5yne were measured using the shake-flask method and values of 2.39 and 2.51 were found, respectively. Autoradiography studies performed on slices of ((R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA)-lesioned rat brains showed a high target-to-background ratio (1.9 ± 0.3). Selectivity and specificity of the binding for the translocator protein was demonstrated using DPA-C5yne (unlabelled), PK11195 and Flumazenil (central benzodiazepine receptor ligand) as competitors. Furthermore, DPA-C5yne proved to be stable in plasma at 37°C for at least 90 min.
CEA, I2BM, Service Hospitalier, Frédéric Joliot, Orsay, France.
Vincent
V
Médran-Navarrete
Nicholas
N
Bernards
Bertrand
B
Kuhnast
Annelaure
A
Damont
Géraldine
G
Pottier
Marie-Anne
MA
Peyronneau
Michael
M
Kassiou
Frank
F
Marguet
Frédéric
F
Puech
Raphaël
R
Boisgard
Frédéric
F
Dollé
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000000981:diagnostic imaging; D009422:Nervous System Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry*; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats
D000081:Acetamides; D005462:Fluorine Radioisotopes; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; C000594949:N,N-diethyl-2-(2-(4-(3-fluoropent-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D011849:Radioactive Tracers
DPA-714; DPA-C5yne; PBR; TSPO 18 kDa; fluorine-18; radiosynthesis