[ 3 H]UR-JG102-A Radiolabeled Cyclic Peptide with High Affinity and Excellent Selectivity for the Neuropeptide Y Y 4 Receptor.

The family of human neuropeptide Y receptors (YRs) comprises four subtypes (Y 1 R, Y 2 R, Y 4 R, and Y 5 R) that are involved in the regulation of numerous physiological processes. Until now, Y 4 R binding studies have been predominantly performed in hypotonic sodium-free buffers using 125 I-labeled derivatives of the endogenous YR agonists pancreatic polypeptide or peptide YY. A few tritium-labeled Y 4 R ligands have been reported; however, when used in buffers containing sodium at a physiological concentration, their Y 4 R affinities are insufficient. Based on the cyclic hexapeptide UR-AK86C, we developed a new tritium-labeled Y 4 R radioligand ([ 3 H]UR-JG102, [ 3 H] 20 ). In sodium-free buffer, [ 3 H] 20 exhibits a very low Y 4 R dissociation constant ( K d 0.012 nM). In sodium-containing buffer (137 mM Na + ), the Y 4 R affinity is lower ( K d 0.11 nM) but still considerably higher compared to previously reported tritiated Y 4 R ligands. Therefore, [ 3 H] 20 represents a useful tool compound for the determination of Y 4 R binding affinities under physiological-like conditions.