title: Robust labeling and comparative preclinical characterization of DOTA-TOC and DOTA-TATE.
abstract: OBJECTIVE
  Various radionuclide-labeled somatostatin analogues are used currently for diagnosis and therapy of neuroendocrine tumors. In particular, [68Ga]Ga-DOTA-TOC is commonly used for diagnosis, while [177Lu]Lu-DOTA-TATE is used for therapy. With the development of theranostics and personalized medicine where the imaging diagnosis is tailored to the subsequent radiotherapy, it is of paramount importance to investigate the relevance of the ligand exchange. The aim of this study was to compare binding capacity of [67/68Ga]Ga-DOTA-TOC ([67/68Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr(ol)) and [67/68Ga]Ga-DOTA-TATE ([67/68Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr) in vitro in monkey brain cryosections and in vivo in the rat, where, in contrast to transfected cell lines, there is a heterogeneous distribution of somatostatin receptor (SSTR) subtypes. The influence of various production methods of [68Ga]Ga-DOTA-TOC and [68Ga]Ga-DOTA-TATE on the biological performance of the tracers was also studied.
  
  
  METHODS
  [67Ga]Ga-DOTA-TOC, [68Ga]Ga-DOTA-TOC, [67Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TATE were synthesized including preconcentration and purification of the generator eluate. The binding of the radioligands was assessed in vitro using autoradiography on cryosections of Rhesus monkey brains and in vivo/ex vivo using organ distribution studies in rats.
  
  
  CONCLUSIONS
  The tracer production method was improved in terms of higher robustness, simplification and good manufacturing practice (GMP) relevance. The synthesis variation did not influence the biological performance of the tracers. There was no statistically significant difference observed in the binding of [67/68Ga]Ga-DOTA-TOC and [67/68Ga]Ga-DOTA-TATE either in brain cortex in vitro or in rat biodistribution and uptake in SSTR-positive tissues such as pancreas, adrenals and pituitary. The uptake in these organs was precluded by the excess of octreotide (Sandostatin). The 10-fold higher affinity to SSTR2 of DOTA-TATE as compared to DOTA-TOC known from studies in transfected cells was reflected in a slightly more intense binding of [67/68Ga]Ga-DOTA-TATE than of [67/68Ga]Ga-DOTA-TOC in the monkey brain sections in vitro, but not in vivo in the rat.
  
  
  CONCLUSIONS
  A robust 68Ga-labeling method was introduced. The difference in the uptake of [67/68Ga]Ga-DOTA-TOC and [67/68Ga]Ga-DOTA-TATE in SSTR2-positive organs was not statistically significant either in vitro in tissue studies or in vivo/ex vivo in rat experiments. The results indicate that the more complex environment in vitro and in vivo diminishes the difference observed in transfected cell line binding.
authors.affiliation: Department of Radiology, Oncology and Radiation Sciences, Uppsala University, PET Center, Uppsala University Hospital, Uppsala, SE-75185 Uppsala, Sweden. irina.velikyan@bms.uu.se
authors.forename: Irina
authors.initials: I
authors.lastname: Velikyan
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Manoj
authors.initials: M
authors.lastname: Nair
authors.forename: Håkan
authors.initials: H
authors.lastname: Hall
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002460:Cell Line; D007553:Isotope Labeling; D008253:Macaca mulatta; D008297:Male; D064847:Multimodal Imaging; D015282:Octreotide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D009942:Organometallic Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: C499142:Ga(III)-DOTATOC; D009942:Organometallic Compounds; D017481:Receptors, Somatostatin; C513399:gallium Ga 68 dotatate; D015282:Octreotide