The effects of novel macrocyclic chelates on the targeting properties of the 68Ga-labeled Gastrin releasing peptide receptor antagonist RM2

Abstract

Background 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. Results 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. Conclusions 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.

Radiometal Complexes as Pharmacokinetic Modifiers: A Potent 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonist Based on the Macrocyclic Metal Chelator NODIA-Me

“…There are two studies reporting the biodistribution of [ 68 Ga]Ga-DOTA-RM2 in mice bearing PC-3 xenografts. , Corresponding data for 1 h p.i. are listed in Table .…”

“…In this respect, the influence of the metal chelator has also been investigated recently for the GRPr. 30 In this study, antagonistic peptide JMV594 was coupled via the 4-amino-1carboxymethyl-piperidine spacer to the chelators AAZTA 5 and DATA 5m to prepare conjugates DATA 5m -RM2 and AAZTA 5 -RM2, respectively. Comparative biodistribution studies with the 68 Ga-labeled compounds, including DOTA-RM2, revealed the influence of the corresponding chelators on the pharmacokinetics and targeting properties.…”

“…This fact can be exploited to use radiometal chelates as handles for radiotracer design. In this respect, the influence of the metal chelator has also been investigated recently for the GRPr . In this study, antagonistic peptide JMV594 was coupled via the 4-amino-1-carboxymethyl-piperidine spacer to the chelators AAZTA 5 and DATA 5m to prepare conjugates DATA 5m -RM2 and AAZTA 5 -RM2, respectively.…”

Radiopharmaceuticals Targeting Gastrin-Releasing Peptide Receptor for Diagnosis and Therapy of Prostate Cancer

“…In a head-to-head comparison with 68 Ga-RM2, 68 Ga-LF1 showed a comparable tumor uptake ( 68 Ga-RM2, 6.51% ± 1.10%ID/g; 68 Ga-LF1, 6.34% ± 0.81%ID/g at 1 h pi) with nearly 1/3 uptake values of the pancreas and a higher tumor-tobackground ratio (including liver, kidney, muscle, blood, and bone) at all time points in biodistribution study. 80 Another well-behaved Sta 13 BBN(6−14)-based radiopharmaceutical, the hydrophilic 68 Ga-118 ( 68 Ga-RM26) with a (PEG) 2 linker, displayed high tumor uptake (8.1% ± 0.4%ID/g at 1 h pi) and fast clearance rate of off-tumor binding (at 1 h pi, small intestine, 1.4% ± 0.5%ID/g, and pancreas, 5.7% ± 0.8%ID/g; at 3 h pi, small intestine, 0.27% ± 0.05%ID/g, and pancreas, 0.6% ± 0.2%ID/g) in PC-3 tumor-bearing mice model. 64,81 Additionally, 68 Ga-RM26 in healthy volunteers showed high absorbed doses in the urinary bladder wall (1.09 mSv/MBq) due to renal excretion mode followed by the pancreas (0.23 mSv/MBq).…”