Details

Autor(en) / Beteiligte

• Nock, Berthold A
• Kaloudi, Aikaterini
• Lymperis, Emmanouil
• Giarika, Athina
• Kulkarni, Harshad R
• Klette, Ingo
• Singh, Aviral
• Krenning, Eric P
• de Jong, Marion
• Maina, Theodosia
• Baum, Richard P

Titel

Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results

Ist Teil von

• Journal of Nuclear Medicine, 2017-01, Vol.58 (1), p.75-80

Ort / Verlag

United States: Society of Nuclear Medicine

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist Ga-SB3 ( Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing excellent tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu -Met -NH dipeptide of SB3 by Sta -Leu -NH , the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting Ga-, In-, and Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using Ga-NeoBOMB1 and PET/CT is also presented. NeoBOMB1 was radiolabeled with Ga, In, and Lu according to published protocols. The respective metalated species Ga-, In-, and Lu-NeoBOMB1 were also synthesized and used in competition binding experiments against [ I-Tyr ]BBN in GRPR-positive PC-3 cell membranes. Internalization of Ga-, In-, and Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37°C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a Ga-, In-, or Lu-NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 μL, 10 pmol total peptide ± 40 nmol Tyr -BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with Ga-NeoBOMB1 were acquired in prostate cancer patients. NeoBOMB1 and Ga-, In-, and Lu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1-2 nM). Ga-, In-, and Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 ( Ga-, In-, and Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 ± 3.9, 28.6 ± 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients, Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging. The GRPR antagonist radioligands Ga-, In-, and Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using Ga-NeoBOMB1 and PET/CT.