Selection of the optimal macrocyclic chelators for labeling with 111 In and 68 Ga improves contrast of HER2 imaging using engineered scaffold protein ADAPT6

• Published in: European journal of pharmaceutics and biopharmaceutics 2019-05, Vol.140, p.109
• Main Authors: von Witting, Emma, Garousi, Javad, Lindbo, Sarah, Vorobyeva, Anzhelika, Altai, Mohamed, Oroujeni, Maryam, Mitran, Bogdan, Orlova, Anna, Hober, Sophia, Tolmachev, Vladimir
• Format: Article
• Language: English
• Subjects: ADAPT; DOTA; DOTAGA; Gallium-68; HER2; Indium-111; NODAGA; NOTA; Radionuclide imaging
• ISSN: 0939-6411; 1873-3441; 1873-3441
• DOI: 10.1016/j.ejpb.2019.05.008

Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with In for SPECT and Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-to-organ ratios. Hence, it was concluded that the best variant for SPECT imaging is In-(HE) DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is Ga-(HE) DANS-ADAPT6-GSSC-NODAGA.