First (18)F-labeled tracer suitable for routine clinical imaging of sst receptor-expressing tumors using positron emission tomography.
OBJECTIVE
Despite excellent radionuclide characteristics, no (18)F-labeled peptides are available for quantitative peptide receptor mapping using positron emission tomography (PET) so far, mainly due to time-consuming multistep radiosyntheses with limited overall yields. A newly developed two-step chemoselective conjugation method allows rapid and high-yield [(18)F]fluorination of peptides via oxime formation and was applied for the synthesis of new (18)F-labeled carbohydrated Tyr(3)-octreotate (TOCA) analogs with optimized pharmacokinetics suitable for clinical routine somatostatin-receptor (sst) imaging.


METHODS
(18)F-labeled glucose (Gluc-S-) and cellobiose (Cel-S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime formation with 4-[(18)F]fluorobenzaldehyde ([(18)F]FBOA-peptides). Both the in vitro internalization profile of Gluc-S-Dpr([(18)F]FBOA)TOCA and Cel-S-Dpr([(18)F]FBOA)TOCA in hsst(2)-expressing Chinese hamster ovary cells (dual tracer protocol) and their biodistribution in AR42J tumor-bearing mice were investigated and compared with two [(18)F]fluoropropionylated ([(18)F]FP) analogs, Gluc-Lys([(18)F]FP)TOCA and Gluc-S-Dpr([(18)F]FP)TOCA.


RESULTS
In contrast to [(18)F]FP-labeling (3 h), chemo-selective [(18)F]FBOA-formation (50 min) afforded the respective radiopeptides in high yields (65-85%). In vitro, Gluc-S-Dpr([(18)F]FBOA)TOCA and Cel-S-Dpr([(18)F]FBOA)-TOCA showed high internalization (139 +/- 2 and 163 +/- 8 of the reference [(125)I]Tyr(3)-octreotide, respectively), which was reflected by high tumor accumulation in vivo [21.8 +/- 1.4 and 24.0 +/- 2.5% of injected dose/g (1 h), respectively]. How-ever, only Cel-S-Dpr([(18)F]FBOA)TOCA and Gluc-S-Dpr([(18)F]FP)TOCA (tumor: 15.1 +/- 1.5% of injected dose/g) with its very low accumulation in all of the nontarget organs showed improved tumor:organ ratios compared with Gluc-Lys([(18)F]FP)TOCA. For Cel-S-Dpr([(18)F]FBOA)TOCA,tumor:organ ratios (1 h) were 42:1, 27:1, 15:1, 3:1, and 208:1 for blood, liver, intestine, kidney, and muscle, respectively.


CONCLUSIONS
Due to the fast and high-yield chemoselective radiofluorination strategy and to its excellent pharmacokinetics, Cel-S-Dpr([(18)F]FBOA)TOCA represents the first tracer suitable for routine clinical application in PET somatostatin receptor imaging.
Schottelius
Margret
M
Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany.
Poethko
Thorsten
T
Herz
Michael
M
Reubi
Jean-Claude
JC
Kessler
Horst
H
Schwaiger
Markus
M
Wester
Hans-Jürgen
HJ
D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006031:Glycosylation; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D009369:Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D010091:Oximes / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D051381:Rats; D017481:Receptors, Somatostatin / Q000096:biosynthesis*; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection
D005462:Fluorine Radioisotopes; D010091:Oximes; D010455:Peptides; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D019788:Fluorodeoxyglucose F18; D005947:Glucose