Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

Abstract

In recent years, implementation of 68 Ga-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of 44 Sc (half-life 5 3.97 h, average b 1 energy [Eb 1 av ] 5 632 keV) as a valuable alternative to 68 Ga (half-life 5 68 min, Eb 1 av 5 830 keV) for imaging and dosimetry before 177 Lu-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotronproduced 44 Sc and its in vitro and in vivo comparison with the 177 Lulabeled pendant. Methods: 44 Sc was produced via the 44 Ca(p,n) 44 Sc nuclear reaction at a cyclotron (17.6 6 1.8 MeV, 50 mA, 30 min) using an enriched 44 Ca target (10 mg 44 CaCO 3 , 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95°C within 10 min. The stability of 44 Sc-cm09 was tested in human plasma. 44 Sc-cm09 was investigated in vitro using folate receptor-positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice Results: Under the given irradiation conditions, 44 Sc was obtained in a maximum yield of 350 MBq at high radionuclide purity (.99%). Semiautomated isolation of 44 Sc from 44 Ca targets allowed formulation of up to 300 MBq of 44 Sc in a volume of 200-400 mL of ammonium acetate/HCl solution (1 M, pH 3.5-4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, 44 Sc-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor-specific binding to KB tumor cells. PET/CT images of mice injected with 44 Sc-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with 44 Sc and 177 Lu revealed almost identical pharmacokinetics. Conclusion: This study presents a highyield production and efficient separation method of 44 Sc at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of 44 Sc for PET imaging. Thus, 44 Sc is a valid alternative to 68 Ga for imaging and dosimetry before 177 Luradionuclide tumor therapy. In the past decade, applications of radiometal-based PET have rapidly increased, particularly for oncologic imaging purposes (1). Clinical implementation of 68 Ga-labeled somatostatin analogs (e.g., 68 Ga-DOTATATE, 68 Ga-DOTATOC) for imaging of neuroendocrine tumors has raised attention because of the excellent imaging quality that can be achieved and the on-site availability of 68 Ga (half-life [T 1/2 ] 5 68 min, average b 1 energy [Eb 1 av ] 5 830 keV, intensity 5 89%) by the 68 Ge/ 68 Ga generator (2-6). Somatostatin receptor-targeted PET is currently used for dosimetry before application of 177 Lu-based radionuclide therapy (7). These facts have established the basis of a new era of PET applicat...

Thermodynamic and Kinetic Study of Scandium(III) Complexes of DTPA and DOTA: A Step Toward Scandium Radiopharmaceuticals

“…It has been shown that DOTA derivatives are suitable ligands for scandium radioisotopes. [18][19] Their oligopeptide, [8,11,[20][21][22] antibody, [23] or other [24,25] conjugates have been investigated for complexation of the scandium radionuclides. Surprisingly, only several studies dealing with structure of DTPA or DOTA scandium(III) complexes have been published.…”

Cyclotron production of high purity 44m,44 Sc with deuterons from 44 CaCO 3 targets

“…Most probes may be more efficient if combined with new radionuclides. Recently, the scandium chemistry has revealed a growing interest with an increasing number of papers available on scandium: from 44 Ti/ 44 Sc generator [1][2][3][4], from neutron irradiated Ti [5,6], cyclotron produced 44m Sc/ 44 Sc [7][8][9], nat Sc [10], 46 Sc [11,12] or 47 Sc [13][14][15]. Among them, the most promising is 44 Sc with a half-life (T 1/2 ) of 3.97 h and mean positron energy of 0.6 MeV ideal for PET cameras.…”

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

“…3) (13). Quality control performed by high-performance liquid chromatography showed the product peak of 47 Sc-cm10, with a retention time of 19.3 min.…”

“…Finally, there is a small-molecular-weight albuminbinding entity (18) integrated in the folate conjugate cm10. This additional functionality was shown to enhance the blood circulation time of folate conjugates and, as a consequence, to improve the tissue distribution profile (13). In the present study, 47 Sc-cm10 was evaluated in vitro using FR-positive KB tumor cells and in vivo by the performance of biodistribution and SPECT/CT studies.…”

“…Folic acid binds selectively to the folate receptor (FR), which is expressed on a variety of tumor types, including cancer of the ovaries and of the lungs (15,16). The DOTA-chelator can be used for stable coordination of Sc as previously demonstrated (13,17). Finally, there is a small-molecular-weight albuminbinding entity (18) integrated in the folate conjugate cm10.…”