Development and preclinical evaluation of [68Ga]Ga-Alb-FAPtp-01, a novel tumour-associated fibroblast activation protein tracer for PET imaging of xenograft glioma

Abstract

\n Purpose\n\nDynamic changes in tumour-associated fibroblast activation protein (FAP) expression in tumours of different stages may be helpful for prognostic evaluation and treatment response monitoring, making this protein a promising surveillance biomarker for timely diagnosis of malignant tumours and effective planning of patient care. Thus, novel FAP-PET imaging tracers were developed and evaluated for the diagnosis of xenograft glioma tumours.\nMethods\n\nTo prospectively verify the prognostic value of the developed FAP tracers, [68Ga]Ga-FAPtp and [68Ga]Ga-Alb-FAPtp-01, measurements of FAP expression and cell uptake and specific binding assays were conducted in U87MG glioma cells. Dynamic/static PET/CT scans were acquired for tumour targeting studies in vivo and in comparison with the reference tracer [68Ga]Ga-FAPI-04 to evaluate diagnostic efficacy. Tumour autoradiography and immunohistochemistry images were acquired to confirm the tracer distribution within the tumour to determine whether it was in accordance with the pathologic data.\nResults\n\nBoth [68Ga]Ga-FAPI-04 and [68Ga]Ga-FAPtp demonstrated marked tumour uptake and comparable pharmaceutical profiles in 1 h dynamic PET scans, and [68Ga]Ga-FAPtp had marginally favourable tumour uptake and less kidney and liver uptake. However, both tracers demonstrated rapid clearance from tumours. Thus, the optimized rationally designed FAP-targeting PET tracer [68Ga]Ga-Alb-FAPtp-01, with albumin binding capability, demonstrated prominent longitudinal tumour uptake in tumour xenografts and displayed significant tumour-to-background contrast over time. The tracer uptake values and T/M ratio were 1.775\u2009±\u20090.179 SUV and T/M\u2009=\u20095.9, 1.533\u2009±\u20090.222 SUV and T/M\u2009=\u20096.7, and 1.425\u2009±\u20090.204 SUV and T/M\u2009=\u20099.5, respectively, at 1 h, 2 h and 3 h. Major organs, such as the heart (0.504\u2009±\u20090.125% ID/g), muscle (0.156\u2009±\u20090.043% ID/g) and brain (0.119\u2009±\u20090.039% ID/g), all displayed comparatively low levels of tracer uptake.\nConclusion\n\nIts improved tumour uptake and pharmacokinetics suggest that the [68Ga]Ga-Alb-FAPtp-01 tracer can noninvasively detect FAP activation in vivo, permitting a precise definition of its roles in tumours of different stages and yielding insights regarding novel FAP-targeted radiotherapeutic strategies at the molecular level.