Abstract The human epidermal growth factor receptor 2 (HER2) is overexpressed in 15–30% of breast cancer cases, plays a significant role in pathogenesis, and has been used as a diagnostic indicator and therapeutic target. Herein, a bioconjugatable porphyrin chelator is described, bearing a water-solubilizing swallowtail motif that projects above and below the plane of the macrocycle. This porphyrin, in various quantities, was reacted in stochastic fashion with the lysine side chains of the anti-HER2 antibody trastuzumab to afford a series of porphyrin–trastuzumab (PorTraz) products with conjugation ratios of 2.3, 3.5, 4.1, and 5.2. Radiolabeling of the conjugates with 64Cu in HEPES buffer (pH 7.2) at 37 °C afforded a molar activity of up to 20 μCi/μg (110 MBq/nmol). Binding was specific to the HER2 receptor, and uptake was observed for each conjugate. In mice bearing HER2+ BT-474 xenografts, PET imaging studies showed significantly higher tumor uptake, with a tumor standardized uptake value (SUV) of 0.95 ± 0.08 versus 0.38 ± 0.12 in the HER2– MDA-MB-468 xenograft control group at 24 h post-injection. PorTraz conjugates showed tumor SUV results of 1.25 ± 0.31 for n = 2.3 porphyrin chelators per antibody and 0.59 ± 0.20 for n = 5.2 porphyrin chelators per antibody. In summary, a series of porphyrin–trastuzumab conjugates were synthesized and labeled with 64Cu, displayed high binding to HER2+ cells, and illustrated uptake in mouse tumor xenografts observable by PET/CT imaging.
