Molecular imaging probes targeting NPY Y₁: Synthesis, structure-activity relationship and radiolabeling of potent and selective small molecules

Objectives New breast specific imaging modalities for use with gamma & positron emitting radiopharmaceuticals have been developed in part in response to high false positive rates associated with traditional anatomical diagnostic imaging methods. Work is now focusing on exploiting breast specific imaging to provide molecular information on breast cancers using targeted agents. Neuropeptide Y (NPY) receptors are over-expressed in several cancers including breast and prostate, which has lead to renewed interest in this receptor family as targets for molecular imaging.

Methods MI probes were synthesized via N-alkylation of a benzimidazole based NPY Y₁ antagonist. Molecules were labeled with ¹²³I and ¹⁸F which were incorporated using iododestannylation and tosyl displacement respectively. Biodistribution studies were performed with nude mice bearing SK-N-MC (NPY Y₁ positive) and MHH-NB-11 (NPY Y₁ negative) xenografts.

Results A series of SAR studies were undertaken which demonstrated that extra heteroatoms on the backbone of the benzimidazole core, short hydrophilic PEGylated side chains are well tolerated (products with K_i values as low as 0.6 nM against NPY Y₁ and >1000 fold selective over NPY Y₂ were identified). Lead compounds were subsequently radiolabeled with either ¹²³I and ¹⁸F in reasonable yields (up to 26% RCY) and high radiochemical purity (>98% RCP In vivo studies showed a maximum uptake of 1.1% ID/g (SK-N-MC, 2 h p.i.) with tumor-to-blood and positive-to negative tumor (SK-N-MC vs. MHH-NB-11) ratios of 1.8:1 and 2.6:1, respectively.

Conclusions A new family of high affinity probes for NPY Y₁ were developed which demonstrated modest but specific target uptake in vivo.