¹⁸F‐labeled 1,2,3‐triazole‐linked Glu‐urea‐Lys‐based PSMA ligands have good pharmacokinetic properties for positron emission tomography imaging of prostate cancer

Abstract

Background: Prostate-specific membrane antigen (PSMA) is increasingly recognized as an excellent target for prostate cancer imaging and therapy. Finding compounds with a high target-to-nontarget ratio are an important challenge in the development of positron emission tomography (PET) imaging agents. In this study, we attempted to find a suitable compound from a simply-synthesized compound library. Method: 18 F-labeling was achieved in a two-step synthesis consisting of [ 18 F]fluorination of azido sulfonates followed by copper(I)-catalyzed click ligation. In vitro binding experiment and in vivo studies were carried out using isogenic PSMA+ PC3-PIP and PSMA− PC3-flu cells and 22RV1 cells. [ 125 I]MIP-1095 was used to measure the binding affinities of compounds through a competitive binding assay, and [ 18 F] DCFPyL was used for a comparative assessment of compounds. Radiation dosimetry data were obtained using OLINDA/EXM software. Results: Nine novel PSMA ligands were synthesized by the combination of three azido compounds and three terminal acetylene-containing Glu-urea-Lys compounds. Among them, compound 6f having a pyridine moiety showed a high binding affinity of 6.51 ± 0.19 nM (K i). 18 F-labeled compounds were obtained at moderate yields within 70 to 75 minutes (including high-performance liquid chromatography purification). Compound [ 18 F]6c had the lowest log P of −2.693. MicroPET/computed tomography (CT) images were acquired from 22RV1 cell xenograft mice after injecting [ 18 F]6c, [ 18 F]6f, and [ 18 F]6i. Additional microPET/CT experiments of [ 18 F]6c and [ 18 F]6f were performed using PSMA+ PC3-PIP and PSMA− PC3-flu cell-bearing mice. [ 18 F]6c was selected for further studies because it was found to have high uptake in tumors and rapid renal clearance, resulting in great tumor-to-nontumor ratios and distinct tumor images with very low background activity. Human dosimetry estimation of [ 18 F]6c using OLINDA/EXM software was calculated, resulting in an effective dose of 4.35 × 10 −3 mSv/MBq. Conclusions: [ 18 F]6c showed significant tumor uptake, a high tumor-to-nontumor ratio, and good radiation dosimetry results, suggesting further development as a potential diagnostic PET agent for prostate cancer.

Comparison of the Effects of DOTA and NOTA Chelators on 64Cu-Cudotadipep and 64Cu-Cunotadipep for Prostate Cancer

“…The dissociation constant ( Kd ) of MIP-1095 was determined via a saturation binding assay. The saturation binding assay was performed as performed in a previous study [ 8 ]. Briefly, the 22Rv1 cells (2 × 10 5 ) were aliquoted into wells in a 24-well plate and incubated with 0.7–17.5 nM (0.0037–0.1332 MBq) of 125 I-MIP-1095 at 37 °C for 1 h. To prevent nonspecific binding, 500 μM unlabeled MIP was added.…”

“…PSMA-specific ligands for PET imaging are frequently labeled with radioactive isotopes, such as 68 Ga and 18 F. The diagnostic radioisotope 68 Ga exhibits a relatively short half-life of 68 min and is produced from either 68 Ge/ 68 Ga-generator or cyclotron [7]. Conversely, 18 F-labeled PSMA compounds exhibit a relatively long half-life of 110 min and are produced in a cyclotron [8][9][10][11][12][13][14]. 64 Cu constitutes another diagnostic radioisotope.…”

Glu-Urea-Lys Scaffold Functionalized Superparamagnetic Iron Oxide Nanoparticles Targeting PSMA for In Vivo Molecular MRI of Prostate Cancer

“…Over the past two decades, many high-affinity antibodies such J415, J533 and J591 [ 12 ], and small molecule tracers such as 99m Tc-MIP-1404/-1405 [ 13 ], [ 18 F]-DCFBC [ 14 ] have been extensively and successfully adopted in developing PCa molecular imaging tracers [ 10 ]. PSMA-targeting small molecular tracers processing Glu-Urea-Lys cores, many of which have been widely explored and exploited in PSMA specific tracers for PCa radiodiagnosis [ 15 , 16 ], exhibited several favorable characteristics, such as high binding affinity, promising target specificity, rapid distribution, and faster blood clearance [ 17 ].…”

Research on preparation and in vitro evaluation of the dendrimer–peptide nuclear acid conjugate for amplification pretargeting

“…25 Compared with linear polymers, the dendrimers can minimize the steric hindrance, thus reducing the accessibility of the conjugated oligomers to their complements due to the spherical geometry of branched polymers and the highly reactive functional groups on the surface. 23 The click-chemistry, copper(I)-catalyzed azide-alkyne cycloaddition, was applied to synthesize 18 F-labeled compounds [26][27][28][29][30] due to the perfect regioselectivity and high chemoselectivity. [31][32][33] Therefore, this study aimed to synthesize 18 F-cPNA via CuAAC click reaction to hybridize with the PNA conjugated PAMAM, generation 4 (G4) (Figure 1) to obtain a higher degree for amplification and evaluate the in vitro properties of the conjugate in solution and on cells.…”