Journal of Labelled Compounds and Radiopharmaceuticals

Nebel, Natascha; Maschauer, Simone; Hocke, Carsten; Hübner, Harald; Gmeiner, Peter; Prante, Olaf

doi: 10.1002/jlcr.3361pmid: 26707848

There is still no efficient fluorine‐18‐labeled dopamine D3 subtype selective receptor ligand for studies with positron emission tomography. We aim at improving the D3 selectivity and hydrophilicity of a candidate ligand by changing the substitution pattern to a 2,3‐dichlorophenylpiperazine and hydroxylation of the butyl chain. The compound (18F)3 exhibited D3 affinity of Ki = 3.6 nM, increased subtype selectivity (Ki(D2/D3) = 60), and low affinity to 5‐HT1A and α1 receptors (Ki (5‐HT1A/D3) = 34; Ki (α1/D3) = 100). The two‐step radiosynthesis was optimized for analog (18F)4 by reducing the necessary concentration of the precursor amine (57 mM), which reacted with (18F)fluorophenylazocarboxylic tert‐butylester under basic conditions. The optimization of the base (Cs 2CO3, 23 mM) and the adjustment of reaction temperature led to the radiochemical yield of 63% after 5 min at 35°C. The optimized reaction conditions were transferred on to the synthesis of (18F)3 with an overall non‐decay corrected yield of 8‐12% in a specific activity of 32‐102 GBq/µmol after a total synthesis time of 30‐35 min. This provides a D 3 radioligand candidate with improved attributes concerning selectivity and radiosynthesis for further preclinical studies.

Collet, Charlotte; Maskali, Fatiha; Clément, Alexandra; Chrétien, Françoise; Poussier, Sylvain; Karcher, Gilles; Marie, Pierre‐Yves; Chapleur, Yves; Lamandé‐Langle, Sandrine

doi: 10.1002/jlcr.3362pmid: 26708055

This work describes the development of new 6‐(18F)fluoro‐carbohydrate‐based prosthetic groups equipped with an azido arm that are able to participate in copper(I)‐catalyzed cycloadditions for 18F labeling of biomolecules under mild conditions. The radiolabeling in high radiochemical yields (up to 68 ± 6%) of these different prosthetic groups is presented. The flexibility of the azido arm introduced on the carbohydrate moieties allows efficient click reactions with different alkyne functionalized peptides such as gluthation or Arg‐Gly‐Asp derivatives in order to prepare glycopeptides. The radiosyntheses of 18F‐labeled glycopeptides proceed in high radiochemical yields (up to 76%) in an automated process with excellent radiochemical purity. The addition of a sugar moiety on peptides should enhance the bioavailability, pharmacokinetic, and in vivo clearance properties of these glycopeptides, compared with the unlabeled native peptide, and these properties are highly favorable for positron emission tomography imaging. A high uptake of 18F‐β‐gluco‐c(RGDfC) is shown by positron emission tomography imaging in a subcutaneous abscess model in the rat, revealing the potential of this tracer to monitor integrin expression as a part of inflammation and/or angiogenesis processes.

Gijs, Marlies; Dammicco, Sylvestre; Warnier, Corentin; Aerts, An; Impens, Nathalie R.E.N; D'Huyvetter, Matthias; Léonard, Marc; Baatout, Sarah; Luxen, André

doi: 10.1002/jlcr.3363pmid: 26712111

One of the most essential aspects to the success of radiopharmaceuticals is an easy and reliable radiolabelling protocol to obtain pure and stable products. In this study, we optimized the bioconjugation and gallium‐68 (68Ga) radiolabelling conditions for a single‐stranded 40‐mer DNA oligonucleotide, in order to obtain highly pure and stable radiolabelled oligonucleotides. Quantitative bioconjugation was obtained for a disulfide‐functionalized oligonucleotide conjugated to the macrocylic bifunctional chelator MMA‐NOTA (maleimido‐mono‐amide (1,4,7‐triazanonane‐1,4,7‐triyl)triacetic acid). Next, this NOTA‐oligonucleotide bioconjugate was radiolabelled at room temperature with purified and pre‐concentrated 68Ga with quantitative levels of radioactive incorporation and high radiochemical and chemical purity. In addition, high chelate stability was observed in physiological‐like conditions (37 °C, PBS and serum), in the presence of a transchelator (EDTA) and transferrin. A specific activity of 51.1 MBq/nmol was reached using a 1470‐fold molar excess bioconjugate over 68Ga. This study presents a fast, straightforward and reliable protocol for the preparation of 68Ga‐radiolabelled DNA oligonucleotides under mild reaction conditions and without the use of organic solvents. The methodology herein developed will be applied to the preparation of oligonucleotidic sequences (aptamers) targeting the human epidermal growth factor receptor 2 (HER2) for cancer imaging.

El‐Kawy, O. A.; Talaat, H. M.

doi: 10.1002/jlcr.3368pmid: 26725469

Hepatocellular carcinoma is a widely prevalent cancer, and hence, the development of radiopharmaceuticals for its management is an important issue. In the current investigation, the complexation of idarubicin with 186Re was studied. Optimum labelling conditions were found to be 4 mg idarubicin, 1.5 mg stannous chloride dihydrate and ~70 MBq Re‐186 at pH 7. The complex showed ~97.6% RCY value at 20 min and remained stable up to 24 h in the presence of 2.5 mg ascorbic acid. Molecular docking was performed to evaluate the complex binding to its target DNA‐human topoisomerase II complex. Result of the in vivo evaluation showed that the complex tends to preferentially localize in cancerous tissues. The in vitro cell growth inhibition assay showed that the effect of the 186Re‐idarubicin was stronger than the effect of cold idarubicin, which strongly suggested that its cytotoxicity was mainly because of radiotoxicity rather than chemotherapeutic activity.