Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

Abstract

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

A General Design Strategy Enabling the Synthesis of Hydrolysis‐Resistant, Water‐Stable Titanium(IV) Complexes

“…The [ 45 Ti]Ti-TREN-CAM and [ 45 Ti]Ti-THP Me complexes both displayed high kinetic inertness in serum, remaining > 98 % intact after 6 h. Albeit not reliably predictive of in vivo stability, these experiments indicate a marked increase in kinetic stability over [Ti 45 ]Ti-DFO ( � 85 % at 6 h) [14a] and [Ti 45 ]Ti-(salan)(CA-PSMA) ( � 80 % at 4 h) is observed for both [ 45 Ti]Ti-TREN-CAM and [ 45 Ti]Ti-THP Me complexes. [22]…”

“…[20,21] Most recently, a prostate specific membrane antigen (PSMA) targeted analog of 45 Ti-(salan)(dipic) has been reported. [22] While this complex displayed increased tumor uptake, significant hydrolysis in buffer and serum was noted, as well as high retention in the blood 3 h post injection, hinting at possible decomplexation and transchelation of the 45 Ti to transferrin in vivo. In addition, the synthesis of these complexes requires organic solvents and high temperature reaction conditions -methods that greatly reduce the potential of these compounds to be clinically translated as radiopharmaceuticals.…”

“…The former could indicate colloid formation, or formation of 45 TiO 2 as shown by Vavere and Welch, [21] while the latter could be caused via trans‐chelation to transferrin [20, 21] . Most recently, a prostate specific membrane antigen (PSMA) targeted analog of 45 Ti‐(salan)(dipic) has been reported [22] . While this complex displayed increased tumor uptake, significant hydrolysis in buffer and serum was noted, as well as high retention in the blood 3 h post injection, hinting at possible decomplexation and transchelation of the 45 Ti to transferrin in vivo.…”

Post-Synthetic Modification Research of Salan Titaniumbis-ChelatesviaSonogashira Reaction

“…使 用 2,6-吡啶二甲酸(2,6-dipicolinic acid, 以下称 Dipic)为 第二刚性配体得到一类七配位的双齿钛配合物 [20] . 其 稳定性突破提升并具有优秀的抗癌活性 [20] , 同位素 [ 45 Ti][SalanTi (IV) Dipic]通过固相合成被制备并具有新型 肿瘤 PET (Positron emission tomography)探针的开发潜 力 [21] , Zhuravlev 等 [22] 近期报道了通过修饰 Dipic, 向 [ 45 Ti][SalanTi (IV) Dipic] 引 入 了 具 癌 细 胞 靶 向 作 用 的 "PSMA"(prostate-specific membrane antigen, 前列腺特 异性膜抗原)的研究工作. 然而"Dipic-PSMA"的制备 途径冗长, 产率较低(四步反应, 总产率 32%), 且原料 价格昂贵, 反应条件苛刻.…”

Thermochromatographic separation of 45Ti and subsequent radiosynthesis of [45Ti]salan

“…Solid phase extraction of 45 Ti dissolved in acidic solutions by ion exchange chromatography is timeconsuming, cannot easily be automated and often results in non-reactive titanyl species that are unsuitable for production of titanium complexes [19,20]. A number of approaches have been proposed to circumvent these problems, which include the use of hydroxamate resins and oxalic acid elution [21], trapping of 45 Ti on a diol-functionalized resin followed by on-resin radiosynthesis [22] and continuous liquid-liquid extraction of the radioisotope with a guaiacol/anisole mixture to obtain a 45 Ti containing organic phase that can be used for radiolabeling [23,24]. Here, we describe an alternative, solvent-free "one-pot" method that is based on thermochromatographic separation of 45 Ti from an irradiated Sc target and consecutive radiotitanation of a salan ligand, thereby obviating the need for organic solvents, solid phase extraction or on-column chelation chemistry.…”