Prototypic18F-Labeled Argininamide-Type Neuropeptide Y Y1R Antagonists as Tracers for PET Imaging of Mammary Carcinoma.
The neuropeptide Y (NPY) Y1receptor (Y1R) selective radioligand (R)-Nα-(2,2-diphenylacetyl)-Nω-[4-(2-[18F]fluoropropanoylamino)butyl]aminocarbonyl-N-(4-hydroxybenzyl)argininamide ([18F]23), derived from the high-affinity Y1R antagonist BIBP3226, was developed for imaging studies of Y1R-positive tumors. Starting from the argininamide core bearing amine-functionalized spacer moieties, a series of fluoropropanoylated and fluorobenzoylated derivatives was synthesized and studied for Y1R affinity. The fluoropropanoylated derivative23displayed high affinity (Ki= 1.3 nM) and selectivity toward Y1R. Radiosynthesis was accomplished via18F-fluoropropanoylation, yielding[18F]23with excellent stability in mice; however, the biodistribution study revealed pronounced hepatobiliary clearance with high accumulation in the gall bladder (>100 %ID/g). Despite the unfavorable biodistribution,[18F]23was successfully used for imaging of Y1R positive MCF-7 tumors in nude mice. Therefore, we suggest[18F]23as a lead for the design of PET ligands with optimized physicochemical properties resulting in more favorable biodistribution and higher Y1R-dependent enrichment in mammary carcinoma.
Department of Pharmaceutical/Medicinal Chemistry II, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstr. 31, D-93053 Regensburg, Germany.
Max
M
Keller
Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, D-91054 Erlangen, Germany.
Simone
S
Maschauer
Department of Pharmaceutical/Medicinal Chemistry II, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstr. 31, D-93053 Regensburg, Germany.
Albert
A
Brennauer
Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, D-91054 Erlangen, Germany.
Philipp
P
Tripal
Department of Pharmaceutical Radiochemistry, Technical University Munich (TUM) , Walther-Meißner-Str. 3, D-85748 Garching, Germany.
Norman
N
Koglin
Department of Obstetrics and Gynecology, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Universitätsstr. 21/23, D-91054 Erlangen, Germany.
Ralf
R
Dittrich
Department of Pharmaceutical/Medicinal Chemistry II, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstr. 31, D-93053 Regensburg, Germany.
Günther
G
Bernhardt
Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, D-91054 Erlangen, Germany.
Torsten
T
Kuwert
Department of Pharmaceutical Radiochemistry, Technical University Munich (TUM) , Walther-Meißner-Str. 3, D-85748 Garching, Germany.
Hans-Jürgen
HJ
Wester
Department of Pharmaceutical/Medicinal Chemistry II, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstr. 31, D-93053 Regensburg, Germany.
Armin
A
Buschauer
Department of Nuclear Medicine, Molecular Imaging and Radiochemistry, Friedrich Alexander University Erlangen-Nürnberg (FAU) , Schwabachanlage 6, D-91054 Erlangen, Germany.
Olaf
O
Prante
Fluorine-18; NPY; PET; Y1R; antagonist; neuropeptide Y; positron emission tomography