Abstract
PurposeCurrent clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features 68Ga-labeled tracers, notably [68Ga]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.MethodsSix 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 [18F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [18F]fluoroethylazide. The 18F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [68Ga]Ga-PSMA-HBED-CC and [18F]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.ResultsF-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 [68Ga]Ga-PSMA-HBED-CC and [18F]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 [68Ga]Ga-PSMA-HBED-CC.ConclusionsSix [18F]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 [68Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these 18F-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.
Highlights
Prostate cancer is the second most prevalent cancer among men, with more than 1.1 million diagnoses in 2012 [1] and more than 292,000 deaths due to prostate cancer reported worldwide in 2013 [2]
Several other characteristics combine to make Prostate-specific membrane antigen (PSMA) an ideal target for molecular diagnostics and therapeutics for prostate cancer: (1) it is overexpressed at all stages of the disease; (2) expression typically correlates with tumor grade, disease aggressiveness, metastasis and biochemical recurrence; (3) it is a transmembrane protein with an extracellular ligand-binding domain; and (4) the bound ligand-protein complex is internalized via receptor-mediated clathrin-dependent endocytosis [7, 8]
In an effort to address the aforementioned challenges in the development of fluorine-18-PSMA ligands of high specificity and affinity, we describe the synthesis and preliminary structure-activity relationship (SAR) studies of two new classes of [18F]fluoroethyltriazolylphenyl urea-based PSMA ligands, afforded by click chemistry in high radiochemical yield (20–40 %), excellent radiochemical purity (>99 %) and high specific activity (182–391 GBq/μmol) from starting activities of less than 7.4 GBq (200 mCi)
Summary
Prostate cancer is the second most prevalent cancer among men, with more than 1.1 million diagnoses in 2012 [1] and more than 292,000 deaths due to prostate cancer reported worldwide in 2013 [2]. Eur J Nucl Med Mol Imaging (2017) 44:647–661 grow—157,000 deaths were reported in 1990 [2]—and it is estimated that more than 180,000 men will be newly diagnosed with prostate cancer in the United States in 2016, and that more than 26,000 deaths due to the disease will be registered [3]. Several other characteristics combine to make PSMA an ideal target for molecular diagnostics and therapeutics for prostate cancer: (1) it is overexpressed at all stages of the disease; (2) expression typically correlates with tumor grade, disease aggressiveness, metastasis and biochemical recurrence; (3) it is a transmembrane protein with an extracellular ligand-binding domain; and (4) the bound ligand-protein complex is internalized via receptor-mediated clathrin-dependent endocytosis [7, 8]. The potential utility of PSMA as a target for diagnostic imaging and therapy was demonstrated with the radiolabeled monoclonal antibody J591 [9], using In-111 or Zr-89 for imaging and Y-90 or Lu177 for therapy, the pharmacokinetics of the antibody make it unsuitable for diagnostic imaging with shortlived radionuclides [10]
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