Bifunctional derivatives of bis(phosphinate)-bearing cyclam (BPC) chelators bearing a carboxylate, amine, isothiocyanate, azide, or cyclooctyne in the BP side chain were synthesized. Conjugations required no protection of phosphinate or ring secondary amine groups. The ring amines were not reactive (proton protected) at pH < ∼8. For isothiocyanate coupling, oligopeptide N-terminal α-amines were more suitable than alkyl amines, e.g., Lys ω-amine (p Ka ∼7.5-8.5 and ∼10-11, respectively) due to lower basicity. The Cu-64 labeling was efficient at room temperature (specific activity ∼100 GBq/μmol; 25 °C, pH 6.2, ∼100 ligand equiv, 10 min). A representative Cu-64-BPC was tested in vivo showing fast clearance and no nonspecific radioactivity deposition. The monoclonal anti-PSCA antibody 7F5 conjugates with thiocyanate BPC derivative or NODAGA were radiolabeled and studied in PC3-PSCA tumor bearing mice by PET. The radiolabeled BPC conjugate was accumulated in the prostate tumor with a low off-target uptake, unlike Cu-64-labeled NODAGA-antibody conjugate. The BPC chelators have a great potential for theranostic applications of the Cu-64/Cu-67 matched pair.

Department of Biophysics and Radiation Biology Semmelweis University Tűzoltó utca 37 47 H 1094 Budapest Hungary

Department of Inorganic Chemistry Faculty of Science Charles University Hlavova 2030 128 40 Prague Czech Republic

German Cancer Research Center Im Neuenheimer Feld 280 69120 Heidelberg Germany

Institute of Radiochemistry and Radioecology University of Pannonia Egyetem St 10 H 8200 Veszprém Hungary

Institute of Radiopharmaceutical Cancer Research Helmholtz Zentrum Dresden Rossendorf Bautzner Landstrasse 400 01328 Dresden Germany

National Center for Tumor Diseases Carl Gustav Carus Technische Universität Dresden Fetscherstrasse 74 01307 Dresden Germany

Partner Site Dresden German Cancer Consortium Fetscherstrasse 74 01307 Dresden Germany

Social Organization for Radioecological Cleanliness P O Box 158 H 8200 Veszprém Hungary

Tumor Immunology University Cancer Center Carl Gustav Carus Technische Universität Dresden Fetscherstrasse 74 01307 Dresden Germany

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Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction