Prototypic 18 F-Labeled Argininamide-Type Neuropeptide Y Y 1 R Antagonists as Tracers for PET Imaging of Mammary Carcinoma.

The neuropeptide Y (NPY) Y1 receptor (Y1 R) selective radioligand ( R )- N α -(2,2-diphenylacetyl)- N ω -[4-(2-[18 F]fluoropropanoylamino)butyl]aminocarbonyl- N -(4-hydroxybenzyl)argininamide ( [ 18 F]23 ), derived from the high-affinity Y1 R antagonist BIBP3226, was developed for imaging studies of Y1 R-positive tumors. Starting from the argininamide core bearing amine-functionalized spacer moieties, a series of fluoropropanoylated and fluorobenzoylated derivatives was synthesized and studied for Y1 R affinity. The fluoropropanoylated derivative 23 displayed high affinity ( K i = 1.3 nM) and selectivity toward Y1 R. Radiosynthesis was accomplished via 18 F-fluoropropanoylation, yielding [ 18 F]23 with 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, [ 18 F]23 was successfully used for imaging of Y1 R positive MCF-7 tumors in nude mice. Therefore, we suggest [ 18 F]23 as a lead for the design of PET ligands with optimized physicochemical properties resulting in more favorable biodistribution and higher Y1 R-dependent enrichment in mammary carcinoma.