title: 99mTc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours.
abstract: OBJECTIVE
  Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA(0),D: Glu(1)]minigastrin (DTPA-MG0) radiolabelled with (111)In and (90)Y, our group developed a (99m)Tc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC(0),D: Glu(1),desGlu(2-6)]minigastrin (HYNIC-MG11).
  
  
  METHODS
  (99m)Tc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice.
  
  
  RESULTS
  Radiolabelling was performed at high specific activities and radiochemical purity was >90%. (99m)Tc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of (99m)Tc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed.
  
  
  CONCLUSIONS
  (99m)Tc-EDDA-HYNIC-MG11 shows advantages over (99m)Tc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement.
authors.affiliation: Clinical Department of Nuclear Medicine, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. elisabeth.vonguggenberg@uki.at
authors.forename: E
authors.initials: E
authors.lastname: von Guggenberg
authors.forename: H
authors.initials: H
authors.lastname: Dietrich
authors.forename: I
authors.initials: I
authors.lastname: Skvortsova
authors.forename: M
authors.initials: M
authors.lastname: Gabriel
authors.forename: I J
authors.initials: IJ
authors.lastname: Virgolini
authors.forename: C
authors.initials: C
authors.lastname: Decristoforo
mesh_terms: D000818:Animals; D018276:Carcinoma, Medullary / Q000000981:diagnostic imaging / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D004492:Edetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D005755:Gastrins; D015972:Gene Expression Regulation, Neoplastic; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007668:Kidney / Q000000981:diagnostic imaging* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D015609:Organotechnetium Compounds; D011877:Radionuclide Imaging; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000096:biosynthesis*; D013667:Technetium; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D005755:Gastrins; D015609:Organotechnetium Compounds; D043887:Receptor, Cholecystokinin B; C525060:technetium 99m HYNIC(0)-Glu(1)-desGlu(2-6)-minigastrin; C008530:minigastrin; C026058:EDDA; D013667:Technetium; D004492:Edetic Acid; D003545:Cysteine; D005998:Glycine; C100184:tricine