Current clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features (68)Ga-labeled tracers, notably [(68)Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer.
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Six triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [(18)F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [(18)F]fluoroethylazide. The (18)F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [(68)Ga]Ga-PSMA-HBED-CC and [(18)F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific.
F-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20-40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC50) ranged from 3-36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6-14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [(68)Ga]Ga-PSMA-HBED-CC and [(18)F]DCFPyL was 5-6 %ID/g at 1-3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [(68)Ga]Ga-PSMA-HBED-CC.
Six [(18)F]triazolylphenyl ureas were prepared in good radiochemical yield. Compounds showed PSMA-specific uptake in LNCaP tumors as high as 14 % ID/g, more than a 2-fold increase over [(68)Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these (18)F-labeled triazoles as well as their promising in vitro and in vivo characteristics make them worthy of clinical development for PET imaging of prostate cancer.
European journal of nuclear medicine and molecular imaging. 2016 Nov 15 [Epub ahead of print]
James Kelly, Alejandro Amor-Coarasa, Anastasia Nikolopoulou, Dohyun Kim, Clarence Williams, Shashikanth Ponnala, John W Babich
Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA., Citigroup Biomedical Imaging Center, Weill Cornell Medicine, New York, NY, 10021, USA., Division of Radiopharmaceutical Sciences and Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, Belfer Research Building, Room 1600, 413 East 69th Street, New York, NY, 10021, USA. .