Amide-to-Triazole Switch vs . In Vivo NEP-Inhibition Approaches to Promote Radiopeptide Targeting of GRPR-Positive Tumors

• Published in: Nuclear medicine and biology 2017-09, Vol.52, p.57-62
• Main Authors: Maina, Theodosia, Kaloudi, Aikaterini, Valverde, Ibai E, Mindt, Thomas L, Nock, Berthold A
• Format: Article
• Language: English
• Subjects: 177Lu-bombesin; Adenocarcinoma; Amides - chemistry; Analogs; Animal models; Animals; Bioavailability; Biodegradability; Biodegradation; Bombesin; Bombesin - chemistry; Bombesin - metabolism; Bombesin - pharmacokinetics; Bombesin - pharmacology; Breast cancer; Cell Line, Tumor; Chemical bonds; Chemical Sciences; Coinjection; Endopeptidases; Gastrin; Gastrin-releasing peptide; Glycopeptides - chemistry; GRPR-radioligand; Heterocyclic Compounds, 1-Ring - chemistry; High-performance liquid chromatography; Humans; In vivo methods and tests; Inhibition; Ligands; Liquid chromatography; Localization; Lung cancer; Male; Mice; Mouse devices; NEP-inhibition; Neprilysin; Neprilysin - antagonists & inhibitors; Peptides; Polyethylene Glycols - chemistry; Prostate cancer; Radioisotopes; Radiology; Receptors, Bombesin - metabolism; Stability; Tissue Distribution; Triazoles - chemistry; Triazolyl-bombesin; Tumor targeting; Tumors; Xenografts
• ISSN: 0969-8051; 1872-9614
• DOI: 10.1016/j.nucmedbio.2017.06.001

Abstract Introduction Radiolabeled bombesin (BBN)-analogs have been proposed for diagnosis and therapy of gastrin-releasing peptide receptor (GRPR)-expressing tumors, such as prostate, breast and lung cancer. Metabolic stability represents a crucial factor for the success of this approach by ensuring sufficient delivery of circulating radioligand to tumor sites. The amide-to-triazole switch on the backbone of DOTA-PEG4 -[Nle14 ]BBN(7–14) ( 1 ) was reported to improve the in vitro stability of resulting177 Lu-radioligands. On the other hand, in-situ inhibition of neutral endopeptidase (NEP) by coinjection of phosphoramidon (PA) was shown to significantly improve the in vivo stability and tumor uptake of biodegradable radiopeptides. We herein compare the impact of the two methods on the bioavailability and localization of177 Lu-DOTA-PEG4 -[Nle14 ]BBN(7–14) analogs in GRPR-positive tumors in mice. Methods The 1,4-disubstituted [1–3]-triazole was used to replace one ( 2 : Gly11 -His12 ; 3 : Ala9 -Val10 ) or two ( 4 : Ala9 -Val10 and Gly11 -His12 ) peptide bonds in 1 (reference) and all compounds were labeled with177 Lu. Each of [177 Lu] 1 – [177 Lu] 4 was injected without (control) or with PA in healthy mice. Blood samples collected 5 min post-injection (pi) were analyzed by HPLC. Biodistribution of [177 Lu] 1 – [177 Lu] 4 was conducted in SCID mice bearing human prostate adenocarcinoma PC-3 xenografts at 4 h pi. Groups of 4 animals were injected with radioligand, alone (controls), or with PA, or with a PA-excess [Tyr4 ]BBN mixture to determine GRPR-specificity of uptake (Block). Results The in vivo stability of the radioligands was: [177 Lu] 1 (25% intact), [177 Lu] 2 (45% intact), [177 Lu] 3 (30% intact) and [177 Lu] 4 (40% intact). By PA-coinjection these values notably increased to 90–93%. Moreover, treatment with PA induced an impressive and GRPR-specific uptake of all radioligands in the PC-3 xenografts at 4 h pi: [177 Lu] 1 : 4.7 ± 0.4 to 24.8 ± 4.9%ID/g; [177 Lu] 2 : 8.3 ± 1.2 to 26.0 ± 1.1%ID/g; [177 Lu] 3 : 6.6 ± 0.4 to 21.3 ± 4.4%ID/g; and [177 Lu] 4 : 4.8 ± 1.6 to 13.7 ± 3.8%ID/g. Conclusions This study has shown that amide-to-triazole substitutions in177 Lu-DOTA-PEG4 -[Nle14 ]BBN(7–14) induced minor effects on bioavailability and tumor uptake in mice models, whereas in-situ NEP-inhibition by PA impressively improved in vivo profiles.