The effects of novel macrocyclic chelates on the targeting properties of the

The gastrin-releasing peptide receptor (GRPr) is a molecular target for the visualization of prostate cancer. Bombesin (BN) analogs are short peptides with a high affinity for GRPr. RM2 is a bombesin-based antagonist. It has been demonstrated that RM2 have superior in vivo biodistribution and targeting properties than high-affinity receptor agonists. This study developed new RM2-like antagonists by introducing the novel bifunctional chelators AAZTA5 and DATA5m to RM2.

The effects of different macrocyclic chelating groups on drug targeting properties and the possibility of preparing 68Ga-radiopharmaceuticals in a kit-based protocol were investigated using 68Ga-labeled entities. Both new RM2 variants were labelled with 68Ga3+ resulting in high yields, stability, and low molarity of the ligand. DATA5m-RM2 and AAZTA5-RM2 incorporated 68Ga3+ nearly quantitatively at room temperature within 3-5 min, and the labelling yield for 68Ga-DOTA-RM2 was approximately 10% under the same conditions. 68Ga-AAZTA5-RM2 showed stronger hydrophilicity according to partition coefficient. Although the maximal cellular uptake values of the three compounds were similar, 68Ga-AAZTA5-RM2 and 68Ga-DATA5m-RM2 peaked more rapidly. Biodistribution studies showed high and specific tumor uptake, with a maximum of 9.12 ± 0.81 percentage injected activity per gram of tissue (%ID/g) for 68Ga-DATA5m-RM2 and 7.82 ± 0.61%ID/g for 68Ga-AAZTA5-RM2 at 30 min after injection.

The conditions for complexation of DATA5m-RM2 and AAZTA5-RM2 with gallium-68 are milder, faster and require less amount of precursors than DOTA-RM2. Chelators had an evident influence on the pharmacokinetics and targeting properties of 68Ga-X-RM2 derivatives. Positively charged 68Ga-DATA5m-RM2 provided a high tumor uptake, high image contrast and good capability of targeting GRPr.