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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.

PubMed | Preclinical PET Platform .
Type: Journal Article | Journal: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | Year: 2014

Systemic amyloidosis is caused by extracellular deposition of insoluble fibrillar proteins arranged in -pleated sheets. [(11)C]PIB has been used in PET studies to assess A deposition in brain of patients with Alzheimers disease (AD). The possibility to visualize other types of amyloid deposits with [(11)C]PIB would be of potential clinical importance in early diagnosis and for following therapeutic effects. In the present study, we evaluated in vitro binding of [(3)H]PIB to tissues containing transthyretin (ATTR), immunoglobulin light-chain (AL), amyloid protein A (AA) and A amyloid. We found significantly higher binding of [(3)H]PIB in tissue from systemic amyloidoses than in control tissue, i.e. 4.7 times higher (p<0.05). [(3)H]PIB showed the highest affinity to cortex of AD brain (IC50=3.84nM), while IC50 values were much higher for ATTR, AA and AL type of amyloidosis and large variations in affinity were observed even within tissues having the same type of amyloidosis. Extraction with guanidine-HCl, which disrupts the -sheet structure, decreased the protein levels and, concomitantly, the binding of [(3)H]PIB in all four types of amyloidoses.

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