title: Optimization of reaction conditions for the radiolabeling of DOTA and DOTA-peptide with (44m/44)Sc and experimental evidence of the feasibility of an in vivo PET generator.
abstract: BACKGROUND
  Among the number of generator systems providing radionuclides with decay parameters promising for imaging and treatment applications, there is the (44)Ti (T1/2=60 years)/(44)Sc (T1/2=3.97 h) generator. This generator provides a longer-lived daughter for extended PET/CT measurements compared to the chemically similar system (68)Ge/(68)Ga. Scandium also exists as (47)Sc, a potential therapeutic radionuclide. It is possible to produce (44)Sc in a cyclotron using, for example, the (44)Ca (d, n) (44)Sc nuclear reaction. In that case, the isomeric state (44 m)Sc (T1/2=58.6h) is co-produced and may be used as an in vivo(44 m)Sc/(44)Sc generator. The aim of this study is to evaluate the feasibility of this in vivo(44 m)Sc/(44)Sc generator and to demonstrate that the daughter radionuclide stays inside the chelator after decay of the parent radionuclide. Indeed, the physico-chemical process occurring after the primary radioactive decay (EC, IT, Auger electron …) has prevented in many cases the use of in-vivo generator, because of the post-effect as described in the literature.
  
  
  METHODS
  The DOTA macrocyclic ligand forms stable complexes with many cations and has been shown to be the most suitable chelating moiety for scandium. Initially, the radiolabeling of DOTA and a DOTA-peptide (DOTATATE) with Sc was performed and optimized as a function of time, pH, metal-to-ligand ratio and temperature. Next, the physico-chemical processes that could occur after the decay (post-effect) were studied. (44 m)Sc(III)-labeled DOTA-peptide was quantitatively adsorbed on a solid phase matrix through a hydrophobic interaction. Elutions were then performed at regular time intervals using a DTPA solution at various concentrations. Finally, the radiolabelled complex stability was studied in serum.
  
  
  RESULTS
  Radiolabeling yields ranged from 90% to 99% for metal-to-ligand ratio ranging from 1:10 to 1:500 for DOTA or DOTATATE respectively. The optimum physico-chemical parameters were pH=4-6, t=20 min, T=70°C. Then, the (44 m)Sc-DOTATATE complex, radiolabeled at 98%, was adsorbed through a hydrophobic interaction to a solid phase. Unlabeled scandium was completely eluted from the column whereas the Sc-DOTATATE complex was 100% retained. The release of (44)Sc from the complex due to decay was less than 1% over 2 periods of (44 m)Sc, independent of the DTPA concentration used for elution. (44 m)Sc/(44)Sc-DOTATATE was stable in serum over 72 h.
  
  
  CONCLUSIONS
  The results indicate that the decay of (44 m)Sc to (44)Sc does not affect the integrity of the radiolabeled compound. Thus the (44 m)Sc/(44)Sc generator is chemically valid and stable in serum. It could be used for PET imaging as an in-vivo generator increasing the life time of the scandium and allowing the use of antibody as labelled compound. Further in-vivo biological evaluations should complete this work.
authors.affiliation: Laboratoire Subatech, UMR 6457, Ecole des Mines de Nantes/CNRS/IN2P3/Université de Nantes, 4 Rue A. Kastler, BP 20722, F-44307 Nantes Cedex 3, France; ARRONAX GIP, 1 rue Aronax, F-44817 Nantes Cedex, France. Electronic address: huclier@subatech.in2p3.fr.
authors.forename: S
authors.initials: S
authors.lastname: Huclier-Markai
authors.affiliation: Laboratoire Subatech, UMR 6457, Ecole des Mines de Nantes/CNRS/IN2P3/Université de Nantes, 4 Rue A. Kastler, BP 20722, F-44307 Nantes Cedex 3, France.
authors.forename: R
authors.initials: R
authors.lastname: Kerdjoudj
authors.affiliation: ARRONAX GIP, 1 rue Aronax, F-44817 Nantes Cedex, France; CRCNA, Inserm/CNRS/Université de Nantes, 8 quai Moncousu, 44007 Nantes Cedex 1, France.
authors.forename: C
authors.initials: C
authors.lastname: Alliot
authors.affiliation: ARRONAX GIP, 1 rue Aronax, F-44817 Nantes Cedex, France.
authors.forename: A C
authors.initials: AC
authors.lastname: Bonraisin
authors.affiliation: ARRONAX GIP, 1 rue Aronax, F-44817 Nantes Cedex, France.
authors.forename: N
authors.initials: N
authors.lastname: Michel
authors.affiliation: Laboratoire Subatech, UMR 6457, Ecole des Mines de Nantes/CNRS/IN2P3/Université de Nantes, 4 Rue A. Kastler, BP 20722, F-44307 Nantes Cedex 3, France; ARRONAX GIP, 1 rue Aronax, F-44817 Nantes Cedex, France.
authors.forename: F
authors.initials: F
authors.lastname: Haddad
authors.affiliation: ARRONAX GIP, 1 rue Aronax, F-44817 Nantes Cedex, France; CRCNA, Inserm/CNRS/Université de Nantes, 8 quai Moncousu, 44007 Nantes Cedex 1, France.
authors.forename: J
authors.initials: J
authors.lastname: Barbet
mesh_terms: D017357:Cyclotrons; D004355:Drug Stability; D005240:Feasibility Studies; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D007553:Isotope Labeling / Q000295:instrumentation / Q000379:methods*; D015282:Octreotide / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes; D012538:Scandium / Q000737:chemistry*
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D015282:Octreotide; D012538:Scandium
keywords: (44)Sc; (44m)Sc; DOTATATE; In vivo generator; PET