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Purpose  Many radioligands have been developed for the visualization of atherosclerosis by targeting inflammation. However, interpretation of in vivo signals is often limited to plaque identification. We evaluated binding of some promising radioligands in an in vitro approach in atherosclerotic plaques with different phenotypes.    Methods  Tissue sections of carotid endarterectomy tissue were characterized as early plaque, fibro-calcific plaque, or phenotypically vulnerable plaque. In vitro binding assays for the radioligands [ 111 In]In-DOTATATE; [ 111 In]In-DOTA-JR11; [ 67 Ga]Ga-Pentixafor; [ 111 In]In-DANBIRT; and [ 111 In]In-EC0800 were conducted, the expression of the radioligand targets was assessed via immunohistochemistry. Radioligand binding and expression of radioligand targets was investigated and compared.    Results  In sections characterized as vulnerable plaque, binding was highest for [ 111 In]In-EC0800; followed by [ 111 In]In-DANBIRT; [ 67 Ga]Ga-Pentixafor; [ 111 In]In-DOTA-JR11; and [ 111 In]In-DOTATATE (0.064 ± 0.036; 0.052 ± 0.029; 0.011 ± 0.003; 0.0066 ± 0.0021; 0.00064 ± 0.00014 %Added activity/mm 2 , respectively). Binding of [ 111 In]In-DANBIRT and [ 111 In]In-EC0800 was highest across plaque phenotypes, binding of [ 111 In]In-DOTA-JR11 and [ 67 Ga]Ga-Pentixafor differed most between plaque phenotypes. Binding of [ 111 In]In-DOTATATE was the lowest across plaque phenotypes. The areas positive for cells expressing the radioligand’s target differed between plaque phenotypes for all targets, with lowest percentage area of expression in early plaque sections and highest in phenotypically vulnerable plaque sections.    Conclusions  Radioligands targeting inflammatory cell markers showed different levels of binding in atherosclerotic plaques and among plaque phenotypes. Different radioligands might be used for plaque detection and discerning early from vulnerable plaque. [ 111 In]In-EC0800 and [ 111 In]In-DANBIRT appear most suitable for plaque detection, while [ 67 Ga]Ga-Pentixafor and [ 111 In]In-DOTA-JR11 might be best suited for differentiation between plaque phenotypes.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13550-021-00772-z.

Autoradiographical assessment of inflammation-targeting radioligands for atherosclerosis imaging: potential for plaque phenotype identification