Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to 90Y Radiolabeling

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• 作者：Mariane Le Fur ; Maryline Beyler ; Nicolas Lepareur ; Olivier Fougère ; Carlos Platas-Iglesias ; Olivier Rousseaux ; Raphaël Tripier
• 刊名：Inorganic Chemistry
• 出版年：2016
• 出版时间：August 15, 2016
• 年：2016
• 卷：55
• 期：16
• 页码：8003-8012
• 全文大小：463K
• 年卷期：0
• ISSN：1520-510X

文摘

The Y³⁺ complex of PCTMB, the tri-n-butyl phosphonate ester of pyclen (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene), was synthesized as well as its Ho³⁺ and Lu³⁺ analogues. X-ray diffraction analyses revealed isomorphous dimeric M₂(PCTMB)₂·9H₂O (M = Y, Ho, Lu) structures that crystallize in the centrosymmetric P1̅ triclinic space group. ¹H NMR and UV studies in aqueous solutions indicated that Y³⁺ complexation is fast, being quantitative in 167 min at pH 3.8 and in 13 min at pH 5.5 (25 °C, acetate buffer, I = 0.150 M, [Y³⁺] = [PCTMB] = 0.2 mM). ¹H NMR DOSY and photon correlation spectroscopy experiments evidenced the formation of aggregates in chloroform with a bimodal distribution that changes slightly with concentration (11–24 and 240–258 nm). The behavior of the acid-assisted dissociation of the complex of Y³⁺ with PCTMB was studied under pseudo-first-order conditions, and the half-life of the [Y(PCTMB)] complex in 0.5 M HCl at 25 °C was found to be 37 min, a value that decreases to 2.6 min in 5 M HCl. The Y³⁺ complex of PCTMB is thermodynamically very stable, with a stability constant of log K_Y-PCTMB = 19.49 and pY = 16.7 measured by potentiometry. ⁹⁰Y complexation studies revealed fast radiolabeling kinetics; optimal radiolabeling conditions were obtained for ⁹⁰Y in acetate medium, PCTMB at 10^–4 to 10^–2 M in acetate buffer pH = 4.75, 15 min at 45–60 °C. In vitro stability studies in human serum showed that [⁹⁰Y(PCTMB)] is quite stable, with about 90% of the activity still in the form of the radiotracer at 24 h and 80% from 48 h to 72 h. A comparison with other ligands such as PCTA, DOTA, and DTPA already used for in vivo application shows that [⁹⁰Y(PCTMB)] is an interesting lipophilic and neutral analogue of these reference chelates for therapeutic applications in aqueous and nonaqueous media.