title: 44Sc-PSMA-617 for radiotheragnostics in tandem with177Lu-PSMA-617-preclinical investigations in comparison with68Ga-PSMA-11 and68Ga-PSMA-617.
abstract: BACKGROUND
  The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging (68Ga) and radionuclide therapy (177Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced44Sc (T1/2= 4.04 h) and investigated preclinically for its use as a diagnostic match to177Lu-PSMA-617.
  
  
  RESULTS
  44Sc was produced at the research cyclotron at PSI by irradiation of enriched44Ca targets, followed by chromatographic separation.44Sc-PSMA-617 was prepared under standard labeling conditions at elevated temperature resulting in a radiochemical purity of >97% at a specific activity of up to 10 MBq/nmol.44Sc-PSMA-617 was evaluated in vitro and compared to the177Lu- and68Ga-labeled match, as well as68Ga-PSMA-11 using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu prostate cancer cells. In these experiments it revealed similar in vitro properties to that of177Lu- and68Ga-labeled PSMA-617. Moreover,44Sc-PSMA-617 bound specifically to PSMA-expressing PC-3 PIP tumor cells, while unspecific binding to PC-3 flu cells was not observed. The radioligands were investigated with regard to their in vivo properties in PC-3 PIP/flu tumor-bearing mice.44Sc-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of44Sc-PSMA-617 resembled that of177Lu-PSMA-617 most closely, while the68Ga-labeled ligands, in particular68Ga-PSMA-11, showed different distribution kinetics.44Sc-PSMA-617 enabled distinct visualization of PC-3 PIP tumor xenografts shortly after injection, with increasing tumor-to-background contrast over time while unspecific uptake in the PC-3 flu tumors was not observed.
  
  
  CONCLUSIONS
  The in vitro characteristics and in vivo kinetics of44Sc-PSMA-617 were more similar to177Lu-PSMA-617 than to68Ga-PSMA-617 and 68Ga-PSMA-11. Due to the almost four-fold longer half-life of44Sc as compared to68Ga, a centralized production of44Sc-PSMA-617 and transport to satellite PET centers would be feasible. These features make44Sc-PSMA-617 particularly appealing for clinical application.
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Umbricht
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland.|Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Benešová
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland.
authors.forename: Raffaella M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Laboratory of Radiochemistry, Paul Scherrer Institut, Villigen-PSI, Switzerland.|Department of Chemistry and Biochemistry University of Bern, Bern, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Türler
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland.|Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland.|Laboratory of Radiochemistry, Paul Scherrer Institut, Villigen-PSI, Switzerland.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: van der Meulen
authors.affiliation: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. cristina.mueller@psi.ch.|Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland. cristina.mueller@psi.ch.
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
keywords: 177Lu; 44Sc; 68Ga; Cyclotron; PET imaging; PSMA; Prostate cancer; Theragnostics