Automated, Resin-Based Method to Enhance the Specific Activity of Fluorine-18 Clicked PET Radiotracers.
Radiolabeling of substrates with 2-[18F]fluoroethylazide exploits the rapid kinetics, chemical selectivity, and mild conditions of the copper-catalyzed azide-alkyne cycloaddition reaction. While this methodology has proven to result in near-quantitative labeling of alkyne-tagged precursors, the relatively small size of the fluoroethylazide group makes separation of the18F-labeled radiotracer and the unreacted precursor challenging, particularly with precursors >500 Da (e.g., peptides). We have developed an inexpensive azide-functionalized resin to rapidly remove unreacted alkyne precursor following the fluoroethylazide labeling reaction and integrated it into a fully automated radiosynthesis platform. We have carried out 2-[18F]fluoroethylazide labeling of four different alkynes ranging from <300 Da to >1700 Da and found that >98% of the unreacted alkyne was removed in less than 20 min at room temperature to afford the final radiotracers at >99% radiochemical purity with specific activities up to >200 GBq/μmol. We have applied this technique to label a novel cyclic peptide previously evolved to bind the Her2 receptor with high affinity, and demonstrated tumor-specific uptake and low nonspecific background by PET/CT. This resin-based methodology is automated, rapid, mild, and general allowing peptide-based fluorine-18 radiotracers to be obtained with clinically relevant specific activities without chromatographic separation and with only a minimal increase in total synthesis time.
Federica
F
Pisaneschi
Lindsay E
LE
Kelderhouse
EvoRx Technologies , 129 North Hill Avenue, Suite 103 Pasadena, California 91106, United States.
Amanda
A
Hardy
Brian J
BJ
Engel
Uday
U
Mukhopadhyay
Carlos
C
Gonzalez-Lepera
Joshua P
JP
Gray
Argentina
A
Ornelas
Department of Chemistry, University of Southern California , 3710 McClintock Avenue, Los Angeles, California 90089, United States.
Terry T
TT
Takahashi
Department of Chemistry, University of Southern California , 3710 McClintock Avenue, Los Angeles, California 90089, United States.
Richard W
RW
Roberts
EvoRx Technologies , 129 North Hill Avenue, Suite 103 Pasadena, California 91106, United States.
Stephen V
SV
Fiacco
David
D
Piwnica-Worms
Steven W
0000-0002-3231-7075
SW
Millward
D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D057930:Click Chemistry / Q000379:methods; D003300:Copper / Q000737:chemistry; D061565:Cycloaddition Reaction / Q000379:methods; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry*; D000072078:Positron Emission Tomography Computed Tomography / Q000379:methods*
D000480:Alkynes; D001386:Azides; D005462:Fluorine Radioisotopes; D010456:Peptides, Cyclic; D003300:Copper