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

István Hajdu; János Angyal; Dezső Szikra; István Kertész; Milo Malanga; Éva Fenyvesi; Lajos Szente; Miklós Vecsernyés; Ildikó Bácskay; Judit Váradi; Pálma Fehér; Zoltán Ujhelyi; Gábor Vasvári; Ágnes Rusznyák; György Trencsényi; Ferenc Fenyvesi

doi:10.1016/j.ejps.2018.12.001

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

Eur J Pharm Sci. 2019 Feb 1:128:202-208. doi: 10.1016/j.ejps.2018.12.001. Epub 2018 Dec 4.

Authors

István Hajdu¹, János Angyal², Dezső Szikra³, István Kertész⁴, Milo Malanga⁵, Éva Fenyvesi⁶, Lajos Szente⁷, Miklós Vecsernyés⁸, Ildikó Bácskay⁹, Judit Váradi¹⁰, Pálma Fehér¹¹, Zoltán Ujhelyi¹², Gábor Vasvári¹³, Ágnes Rusznyák¹⁴, György Trencsényi¹⁵, Ferenc Fenyvesi¹⁶

Affiliations

¹ Division of Nuclear Medicine, Medical Imaging Department Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
² Department of Periodontology, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
³ Division of Nuclear Medicine, Medical Imaging Department Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
⁴ Division of Nuclear Medicine, Medical Imaging Department Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
⁵ Cyclolab Cyclodextrin R&D Laboratory Ltd., H-1097, Illatos St. 7, Budapest, Hungary.
⁶ Cyclolab Cyclodextrin R&D Laboratory Ltd., H-1097, Illatos St. 7, Budapest, Hungary. Electronic address: [email protected].
⁷ Cyclolab Cyclodextrin R&D Laboratory Ltd., H-1097, Illatos St. 7, Budapest, Hungary. Electronic address: [email protected].
⁸ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
⁹ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹⁰ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹¹ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹² Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹³ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹⁴ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹⁵ Division of Nuclear Medicine, Medical Imaging Department Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].
¹⁶ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: [email protected].

PMID: 30521943
DOI: 10.1016/j.ejps.2018.12.001

Abstract

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.

Keywords: (68)Ga; Hydroxypropyl-beta-cyclodextrin; Pharmacokinetics; Positron emission tomography.

MeSH terms

2-Hydroxypropyl-beta-cyclodextrin / chemistry*
2-Hydroxypropyl-beta-cyclodextrin / pharmacology*
Acetates / chemistry*
Acetates / pharmacology*
Animals
Gallium / chemistry*
Heterocyclic Compounds, 1-Ring / chemistry*
Heterocyclic Compounds, 1-Ring / pharmacology*
Male
Mice
Mice, Inbred BALB C
Molecular Structure
Radiopharmaceuticals / chemical synthesis
Radiopharmaceuticals / chemistry
Radiopharmaceuticals / pharmacology

Substances

1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
Acetates
Heterocyclic Compounds, 1-Ring
Radiopharmaceuticals
2-Hydroxypropyl-beta-cyclodextrin
Gallium