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Aim  Elevated kidney uptake in insulinoma patients remains a major limitation of radiometallated exendin-derived ligands of the glucagon-like peptide 1 receptor (GLP-1R). Based on the previously published potent GLP-1R-activating undecapeptide  1 , short-chained GLP-1R ligands were developed to investigate whether kidney uptake can be reduced by means of direct  18 F-labeling (nuclide-based accelerated renal excretion) or the reduction of the overall ligand charge (ligand-based reduced kidney uptake).    Materials & methods  GLP-1R ligands were prepared according to optimized standard protocols via solid-phase peptide synthesis (SPPS) or, when not practicable, via fragment coupling in solution. Synthesis of (2‘-Et, 4‘-OMe)4, 4’-L-biphenylalanine ((2′-Et, 4′-OMe)BIP), required for the preparation of  1 , was accomplished by Suzuki-Miyaura cross-coupling. In vitro experiments were performed using stably transfected GLP-1R +  HEK293-hGLP-1R cells.    Results  In contrast to the three reference ligands glucagon-like peptide 1 (GLP-1, IC 50  = 23.2 ± 12.2 nM), [Nle 14 , Tyr(3-I) 40 ]exendin-4 (IC 50  = 7.63 ± 2.78 nM) and [Nle 14 , Tyr 40 ]exendin-4 (IC 50  = 9.87 ± 1.82 nM), the investigated GLP-1R-targeting small peptides (9–15 amino acids), including lead peptide  1 , exhibited only medium to low affinities (IC 50  > 189 nM). Only SiFA-tagged undecapeptide  5  (IC 50  = 189 ± 35 nM) revealed a higher affinity than  1  (IC 50  = 669 ± 242 nM).    Conclusion  The investigated small peptides, including lead peptide  1  ,  could not compete with favorable in vitro characteristics of glucagon-like peptide 1 (GLP-1), [Nle 14 , Tyr(3-I) 40 ]exendin-4 and [Nle 14 , Tyr 40 ]exendin-4. The auspicious EC 50  values of  1  provided by the literature could not be transferred to competitive binding experiments. Therefore, the use of  1  as a basic scaffold for the design of further GLP-1R-targeting radioligands cannot be recommended. Further investigations might include the scaffold of  5 , although substantial optimizations concerning affinity and lipophilicity would be required. In sum, GLP-1R-targeting radioligands with reduced kidney uptake could not be obtained in this work, which emphasizes the need for further ligands addressing this particular issue.    Supplementary Information  The online version contains supplementary material available at 10.1186/s41181-021-00136-x.

Small peptide-based GLP-1R ligands: an approach to reduce the kidney uptake of radiolabeled GLP-1R-targeting agents?