We have recently introduced the potent GRPR-antagonist [(68)Ga]SB3 ([(68)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 the novel GRPR-antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biological profile of resulting [(67/68)Ga/(111)In/(177)Lu]NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. First evidence of prostate cancer lesion visualization in man with [(68)Ga]NeoBOMB1 and PET/CT is also presented.
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NeoBOMB1 was radiolabeled with (67/68)Ga, (111)In and (177)Lu according to published protocols. The respective metalated species [natGa/natIn/natLu]NeoBOMB1 were also synthesized and used in competition binding experiments against [(125)I-Tyr4]BBN in GRPR-positive PC-3 cell membranes. Internalization of [(67)Ga/(111)In/(177)Lu]NeoBOMB1 radioligands was studied in PC-3 cells at 370C and their metabolic stability in peripheral mouse blood was determined by HPLC-analysis of blood samples. Biodistribution was performed by injecting a [(67)Ga/(111)In/(177)Lu]NeoBOMB1 bolus (74 kBq/74 kBq /370 kBq, respectively, 100 µL, 10 pmol total peptide ±40 nmol [Tyr4]BBN: for in vivo GRPR-blockade) in SCID mice bearing PC-3 xenografts. PET/CT images with [(68)Ga]NeoBOMB1 were acquired in prostate cancer patients.
NeoBOMB1 and [natGa/natIn/natLu]NeoBOMB1 bound to GRPR with high affinity (IC50: 1-2 nM). [(67)Ga/(111)In/(177)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 postinjection (pi)). After injection in mice, all three [(67)Ga/(111)In/(177)Lu]NeoBOMB1 showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g. 30.6±3.9%ID/g, 28.6±6.0%ID/g and >35%ID/g at 4 h pi, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients [(68)Ga]NeoBOMB1 rapidly localized in pathological lesions achieving high contrast imaging.
The GRPR-antagonist radioligands [(67)Ga/(111)In/(177)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 man applying [(68)Ga]NeoBOMB1 and PET/CT.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2016 Aug 04 [Epub ahead of print]
Berthold Artur Nock, Aikaterini Kaloudi, Emmanouil Lymperis, Athina Giarika, Harshad Rajaram Kulkarni, Ingo Klette, Aviral Singh, Eric P Krenning, Marion de Jong, Theodosia Maina-Nock, Richard P Baum
NCSR "Demokritos", Greece;, NCSR "Demokritos", Greece;, NCSR "Demokritos", Greece;, NCSR "Demokritos", Greece;, ZENTRALKLINIK BAD BERKA, Germany;, Zentralklinik Bad Berka;, Zentralklinik Bad Berka;, Erasmus University Medical Center Rotterdam, Netherlands;, Erasmus MC, Netherlands;, NCSR "Demokritos", Greece;, Zentralklink Bad Berka, Germany.