Abstract
The neuropeptide Y (NPY) Y(1) receptor (Y(1)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 Y(1)R antagonist BIBP3226, was developed for imaging studies of Y(1)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 Y(1)R affinity. The fluoropropanoylated derivative 23 displayed high affinity (K(i) = 1.3 nM) and selectivity toward Y(1)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 Y(1)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 Y(1)R-dependent enrichment in mammary carcinoma.