RESUMEN
This research presents the development of positron emission tomography (PET) radiotracers for detecting Mycobacterium tuberculosis (MTB) for the diagnosis and monitoring of tuberculosis. Two phage display-derived peptides with proven selective binding to MTB were identified for development into PET radiopharmaceuticals: H8 (linear peptide) and PH1 (cyclic peptide). We sought to functionalize H8/PH1 with NODASA, a bifunctional chelator that allows complexation of PET-compatible radiometals such as gallium-68. Herein, we report on the chelator functionalization, optimized radiosynthesis, and assessment of the radiopharmaceutical properties of [68Ga]Ga-NODASA-H8 and [68Ga]Ga-NODASA-PH1. Robust radiolabeling was achieved using the established routine method, indicating consistent production of a radiochemically pure product (RCP ≥ 99.6%). For respective [68Ga]Ga-NODASA-H8 and [68Ga]Ga-NODASA-PH1, relatively high levels of decay-corrected radiochemical yield (91.2% ± 2.3%, 86.7% ± 4.0%) and apparent molar activity (Am, 3.9 ± 0.8 and 34.0 ± 5.3 GBq/µmol) were reliably achieved within 42 min, suitable for imaging purposes. Notably, [68Ga]Ga-NODASA-PH1 remained stable in blood plasma for up to 2 h, while [68Ga]Ga-NODASA-H8 degraded within 30 min. For both 68Ga peptides, minimal whole-blood cell binding and plasma protein binding were observed, indicating a favorable pharmaceutical behavior. [68Ga]Ga-NODASA-PH1 is a promising candidate for further in vitro/in vivo evaluation as a tuberculosis-specific infection imaging agent.
RESUMEN
PURPOSE: Nuclear imaging is an important preclinical research tool to study infectious diseases in vivo and could be extended to investigate complex aspects of malaria infections. As such, we report for the first time successful radiolabeling of a novel antibody specific to Plasmodium-infected erythrocytes (IIIB6), its in vitro assessment and molecular imaging in nude mice. PROCEDURES: In vitro confocal microscopy was used to determine the stage-specificity of Plasmodium-infected erythrocytes recognised by IIIB6. To enable micro-positron emission tomography (PET)/X-ray computed tomography (CT) imaging, IIIB6 was conjugated to Bz-DFO-NCS and subsequently radiolabeled with zirconium-89. Healthy nude mice were injected with [89Zr]IIIB6, and pharmacokinetics and organ uptake were monitored over 24 h. This was followed by post-mortem animal dissection to determine the biodistribution of [89Zr]IIIB6. RESULTS: IIIB6 recognised all the relevant stages of Plasmodium falciparum-infected erythrocytes (trophozoites, schizonts and gametocytes) that are responsible for severe malaria pathology. [89Zr]IIIB6-radiolabeling yields were efficient at 84-89 %. Blood pool imaging analysis indicated a pharmacological half-life of 9.6 ± 2.5 h for [89Zr]IIIB6. The highest standard uptake values were determined at 2-6 h in the liver followed by the spleen, kidneys, heart, stomach and lung, respectively. Minimal activity was present in muscle and bone tissues. CONCLUSION: In vitro characterization of IIIB6 and pharmacokinetic characterization of [89Zr]IIIB6 revealed that this antibody has potential for future use in Plasmodium-infected mouse models to study malaria in a preclinical in vivo setting with PET/CT imaging.