Radiochemical synthesis and preclinical evaluation of 68Ga-labeled NODAGA-hydroxypropyl-beta-cyclodextrin (68Ga-NODAGA-HPBCD)

• Published in: European journal of pharmaceutical sciences 2019-02, Vol.128, p.202-208
• Main Authors: Hajdu, István, Angyal, János, Szikra, Dezső, Kertész, István, Malanga, Milo, Fenyvesi, Éva, Szente, Lajos, Vecsernyés, Miklós, Bácskay, Ildikó, Váradi, Judit, Fehér, Pálma, Ujhelyi, Zoltán, Vasvári, Gábor, Rusznyák, Ágnes, Trencsényi, György, Fenyvesi, Ferenc
• Format: Article
• Language: English
• Subjects: 68Ga; Hydroxypropyl-beta-cyclodextrin; Pharmacokinetics; Positron emission tomography
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2018.12.001

A new renaissance started in the research and application of cyclodextrins a few years ago. 2-Hydroxypropyl-beta-cyclodextrin (HPBCD) is used in the formulation of drugs and recently orphan designation was granted for the treatment of Niemann-Pick disease, type C. HPBCD is considered to be safe, but the exact mechanism of action and side effects are not completely explained. Labeled cyclodextrin derivatives are required to reveal the biological activity and in vivo distribution by imaging techniques. The aims of our study were to synthetize the 68Ga-labeled NODAGA-hydroxypropyl-beta-cyclodextrin (68Ga-NODAGA-HPBCD) and test the pharmacokinetic properties and in vivo distribution of this radiolabeled molecule. p-NCS-benzyl-NODA-GA (NODAGA) was conjugated to the 6-deoxy-6-monoamino-(2-hydroxypropyl)-β-cyclodextrin (NH2-HPBCD). The product (NODAGA-HPBCD) was analyzed by analytical RP-HPLC and verified with high resolution mass spectrometry. In the next step the NODAGA-HPBCD was labeled with Gallium-68 (68Ga). The 68Ga labeled NODAGA-HPBCD (68Ga-NODAGA-HPBCD) was characterized and the radiochemical purity (RCP%), partition coefficient (log P values), and in vitro stability was determined. Thereafter in vivo distribution and pharmacokinetic properties of 68Ga-NODAGA-HPBCD was monitored by positron emission tomography (PET). NODAGA-HPBCD was purified by preparative RP-HPLC and the purity was better than 98%. The radiochemical purity of the 68Ga-NODAGA-HPBCD was higher than 98%, the specific activity was 17.62 ± 2.43 GBq/μmol, and the decay corrected yield was 76.54 ± 6.12% (n = 8). The octanol/water partition coefficient of 68Ga labeled NODAGA-HPBCD was found to be −3.07 ± 0.11. In vivo dynamic and ex vivo biodistribution studies using control BALB/c mice revealed that 68Ga labeled NODAGA-HPBCD was mainly excreted by the kidney, due to its hydrophilic properties that has been proved by the partition coefficient. The accumulation of the radiotracer in abdominal organs was low, and no uptake was found in the brain. In conclusion 68Ga labeled NODAGA-HPBCD was successfully produced for the first time and tested in vitro and in vivo. The synthesized NODAGA-HPBCD was characterized and labeled with 68Ga successfully. Overall, the outcome of our study indicates that the in vivo behavior of radiolabeled cyclodextrins can be examined by PET techniques, thus these derivatives are suitable for further pharmacokinetic measurements. [Display omitted]