PT - JOURNAL ARTICLE AU - Xiong, Chiyi AU - Du, Yong AU - Cao, Qizhen AU - Alpay, Merve AU - Mohan, Chandra AU - Li, Chun TI - <em>Two stage µPET/CT imaging of TCO-anti-CD11b with a<sup>64</sup>Cu-NOTA-tetrazine tracer to monitor anti-GBM and lupus nephritis</em> DP - 2019 May 01 TA - Journal of Nuclear Medicine PG - 340--340 VI - 60 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/60/supplement_1/340.short 4100 - http://jnm.snmjournals.org/content/60/supplement_1/340.full SO - J Nucl Med2019 May 01; 60 AB - 340Objectives: The hallmark of systemic lupus erythematosus (SLE) is the infiltration of immune cells into the kidneys, which cause tissue damage and proteinuria. PET/CT with radiolabeled anti-CD11b antibody may be used to monitor the progression of the disease because of high expression of CD11b on the surface of innate immune cells. However, it is challenging to detect nephritis using radiolabeled antibodies due to high uptake of radiotracers in the liver and the spleen. The purpose of this study was to investigate whether a two-stage targeting approach could improve signal to background ratio in preclinical models of lupus nephritis. Methods: 64Cu labeled tetrazine (64Cu-NOTA-tetrazine) and transcyclooctene (TCO) modified anti-CD11b (TCO-anti-CD11b) were synthesized and characterized. Two murine nephritis models, one with anti-glomerular basement membrane antibody-induced disease and another with spontaneous lupus disease in MRL/MP-Fasipr/ Fasipr mice were used for in vivo evaluation of the click reaction between TCO-anti-CD11b and 64Cu-NOTA-tetrazine. TCO-anti-CD11b was injected intravenously (i.v.), followed by i.v. injection of 64Cu-NOTA-tetrazine 24 h later. MicroPET/CT images were acquired at 4 h and 24 h post-radiotracer injection. Normal mice and diseased mice without prior injection of TCO-anti-CD11b were used as controls. Results: The click reaction between TCO-anti-CD11b and 64Cu-NOTA-tetrazine was 90% complete after 30 min in PBS at 37°C. In both animal models of SLE, microPET/CT clearly indicated that 64Cu-NOTA-tetrazine uptake was significantly higher in the inflamed kidneys than in normal kidneys. Moreover, there was significantly higher uptake of radiotracer in diseased mice pre-injected with TCO-anti-CD11b than in mice without pre-injection of TCO-anti-CD11b. Compared to directly radiolabeled anti-CD11b, two-stage targeting with the TCO-anti-CD11b/64Cu-NOTA-tetrazine system showed higher kidney-to-liver and kidney-to-spleen ratios, resulting in better delineation of diseased kidneys with lower background signal. Conclusions: Anti-GBM and lupus nephritis were both successfully imaged by microPET/CT using a two-stage targeting strategy with the TCO-anti-CD11b/64Cu-NOTA-tetrazine system. Further studies are warranted to optimize these biorthogonal reactants for imaging and organ inflammation in autoimmune diseases. Key Words: CD11b, PET imaging, Copper-64, Pretargeting