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

In recent years, implementation of Ga-68-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of Sc-44 (half-life = 3.97 h, average beta(+) energy [E beta(+)(av)] = 632 keV) as a valuable alternative to Ga-68 (half-life = 68 min, E beta(+)(av) = 830 key) for imaging and dosimetry before Lu-177-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced Sc-44 and its in vitro and in vivo comparison with the Lu-177-labeled pendant. Methods: Sc-44 was produced via the Ca-44(p,n)Sc-44 nuclear reaction at a cyclotron (17.6 +/- 1.8 MeV, 50 mu A, 30 min) using an enriched Ca-44 target (10 mg (CaCO3)-Ca-44, 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 degrees C within 10 min. The stability of Sc-44-cm09 was tested in human plasma. Sc-44-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, Sc-44 was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of Sc-44 from Ca-44 targets allowed formulation of up to 300 MBq of Sc-44 in a volume of 200-400 mu L 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, Sc-44-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 Sc-44-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with Sc-44 and Lu-177 revealed almost identical pharmacokinetics. Conclusion: This study presents a high-yield production and efficient separation method of Sc-44 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 Sc-44 for PET imaging. Thus, Sc-44 is a valid alternative to Ga-68 for imaging and dosimetry before Lu-177-radionuclide tumor therapy.