title: 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 = 3.97 h, average β(+) energy [Eβ(+)av] = 632 keV) as a valuable alternative to (68)Ga (half-life = 68 min, Eβ(+)av = 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 cyclotron-produced (44)Sc and its in vitro and in vivo comparison with the (177)Lu-labeled pendant.
  
  
  METHODS
  (44)Sc was produced via the (44)Ca(p,n)(44)Sc nuclear reaction at a cyclotron (17.6 ± 1.8 MeV, 50 μA, 30 min) using an enriched (44)Ca target (10 mg (44)CaCO3, 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 μL 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.
  
  
  CONCLUSIONS
  This study presents a high-yield 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)Lu-radionuclide tumor therapy.
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, Villigen-PSI, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Maruta
authors.initials: M
authors.lastname: Bunka
authors.forename: Josefine
authors.initials: J
authors.lastname: Reber
authors.forename: Cindy
authors.initials: C
authors.lastname: Fischer
authors.forename: Konstantin
authors.initials: K
authors.lastname: Zhernosekov
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
mesh_terms: D000818:Animals; D001610:Beta Particles; D002614:Chelating Agents / Q000737:chemistry; D017357:Cyclotrons; D005240:Feasibility Studies; D005260:Female; D005492:Folic Acid / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D007553:Isotope Labeling; D007624:KB Cells; D008187:Lutetium; D051379:Mice; D049268:Positron-Emission Tomography; D011854:Radiochemistry / Q000295:instrumentation*; D011868:Radioisotopes; D012538:Scandium / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; D005492:Folic Acid; D012538:Scandium
keywords: 44Sc; PET; cyclotron; folate radioconjugate; folate receptor