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Varasteh Z.,Preclinical PET Platform | Velikyan I.,Preclinical PET Platform | Velikyan I.,Uppsala University | Velikyan I.,Uppsala University Hospital | And 9 more authors.
Bioconjugate Chemistry | Year: 2013

The gastrin-releasing peptide receptor (GRPR/BB2) is a molecular target for the visualization of prostate cancer. This work focused on the development of high-affinity, hydrophilic, antagonistic, bombesin-based imaging agents for PET and SPECT. The bombesin antagonist analog d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu- NH2 ([d-Phe6,Sta13,Leu14]bombesin[6- 14]) was synthesized and conjugated to 1,4,7-triazacyclononane-N,N′, N″-triacetic acid (NOTA) via a diethylene glycol (PEG2) linker. The resulting conjugate, NOTA-PEG2-[d-Phe6,Sta 13,Leu14]bombesin[6-14] (NOTA-P2-RM26), was labeled with 68Ga (T1/2 = 68 min, positron emitter) and 111In (T1/2 = 2.8 days, gamma emitter). The labeling stability, specificity, inhibition efficiency (IC50), and dissociation constant (KD) of both labeled compounds as well as their cellular retention and internalization were investigated. The pharmacokinetics of the dual isotope (111In/68Ga)-labeled peptide in both normal NMRI mice and PC-3 tumor-bearing Balb/c nu/nu mice was also studied. NOTA-P2-RM26 was labeled with 111In and 68Ga at a radiochemical yield of >98%. Both conjugates were shown to have high specificity and binding affinity for GRPR. The KD value was determined to be 23 ± 13 pM for the 111In-labeled compound in a saturation binding experiment. In addition, natIn- and natGa-NOTA-P2-RM26 showed low nanomolar binding inhibition concentrations (IC50 = 1.24 ± 0.29 nM and 0.91 ± 0.19 nM, respectively) in a competitive binding assay. The internalization rate of the radiolabeled conjugates was slow. The radiometal-labeled tracers demonstrated rapid blood clearance via the kidney and GRPR-specific uptake in the pancreas in normal mice. Tumor targeting and biodistribution studies in mice bearing PC-3 xenografts displayed high and specific uptake in tumors (8.1 ± 0.4%ID/g for 68Ga and 5.7 ± 0.3%ID/g for 111In) and high tumor-to-background ratios (tumor/blood: 12 ± 1 for 68Ga and 10 ± 1 for 111In) after only 1 h p.i. of 45 pmol of peptide. The xenografts were visualized by gamma and microPET cameras shortly after injection. In conclusion, the antagonistic bombesin analog NOTA-PEG2-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (NOTA-P2-RM26) is a promisindg candidate for prostate cancer imaging using PET and SPECT/CT. © 2013 American Chemical Society.

Akerbladh L.,Organic Pharmaceutical Chemistry | Nordeman P.,Organic Pharmaceutical Chemistry | Wejdemar M.,Organic Pharmaceutical Chemistry | Odell L.R.,Organic Pharmaceutical Chemistry | Larhed M.,Uppsala University
Journal of Organic Chemistry | Year: 2015

A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products after only 20 min of microwave (MW) heating at 120 °C. The second method (B) is a gas-free one-pot two-step sequence which runs at room temperature, allowing the use of sensitive substituents (e.g., nitro and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid source of CO. © 2015 American Chemical Society.

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