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Background: Fibroblast activation protein (FAP), a transmembrane serine protease overexpressed by cancer-associated fibroblasts in the tumor stroma, is an interesting biomarker for targeted radionuclide theranostics. FAP-targeting radiotracers have demonstrated to be superior to [18F]FDG PET/CT in various solid cancers. However, these radiotracers have suboptimal tumor retention for targeted radionuclide therapy (TRT). We aimed to develop a novel FAP-targeting pharmacophore with improved pharmacokinetics by introducing a substitution at the 8-position of (4-quinolinoyl)-glycyl-2-cyanopyrrolidine, which allows for conjugation of a chelator, dye, or other payloads. Results: Here we showed the synthesis of DOTA-conjugated eFAP-6 and sulfo-Cyanine5-conjugated eFAP-7. After chemical characterization, the uptake and specificity of both tracers were determined on FAP-expressing cells. In vitro, [111In]In-eFAP-6 demonstrated a superior affinity and a more rapid, although slightly lower, peak uptake than gold standard [111In]In-FAPI-46. Confocal microscopy demonstrated a quick FAP-mediated internalization of eFAP-7. Studies with HT1080-huFAP xenografted mice confirmed a more rapid uptake of [177Lu]Lu-eFAP-6 vs. [177Lu]Lu-FAPI-46. However, tumor retention at 24 h post injection of [177Lu]Lu-eFAP-6 was lower than that of [177Lu]Lu-FAPI-46, hereby currently limiting its use for TRT. Conclusion: The superior affinity and faster tumor accumulation of eFAP-6 over FAPI-46 makes it a suitable compound for radionuclide imaging. After further optimization, the eFAP series has great potential for various oncological interventions, including fluorescent-guided surgery and effective targeted radionuclide theranostics. [ABSTRACT FROM AUTHOR]

Abstract Background Fibroblast activation protein (FAP), a transmembrane serine protease overexpressed by cancer-associated fibroblasts in the tumor stroma, is an interesting biomarker for targeted radionuclide theranostics. FAP-targeting radiotracers have demonstrated to be superior to [18F]FDG PET/CT in various solid cancers. However, these radiotracers have suboptimal tumor retention for targeted radionuclide therapy (TRT). We aimed to develop a novel FAP-targeting pharmacophore with improved pharmacokinetics by introducing a substitution at the 8-position of (4-quinolinoyl)-glycyl-2-cyanopyrrolidine, which allows for conjugation of a chelator, dye, or other payloads. Results Here we showed the synthesis of DOTA-conjugated eFAP-6 and sulfo-Cyanine5-conjugated eFAP-7. After chemical characterization, the uptake and specificity of both tracers were determined on FAP-expressing cells. In vitro, [111In]In-eFAP-6 demonstrated a superior affinity and a more rapid, although slightly lower, peak uptake than gold standard [111In]In-FAPI-46. Confocal microscopy demonstrated a quick FAP-mediated internalization of eFAP-7. Studies with HT1080-huFAP xenografted mice confirmed a more rapid uptake of [177Lu]Lu-eFAP-6 vs. [177Lu]Lu-FAPI-46. However, tumor retention at 24 h post injection of [177Lu]Lu-eFAP-6 was lower than that of [177Lu]Lu-FAPI-46, hereby currently limiting its use for TRT. Conclusion The superior affinity and faster tumor accumulation of eFAP-6 over FAPI-46 makes it a suitable compound for radionuclide imaging. After further optimization, the eFAP series has great potential for various oncological interventions, including fluorescent-guided surgery and effective targeted radionuclide theranostics.

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumours and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumour such as prostate cancer requires the expansion of existing and the establishment of new theranostics centres. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostics centres. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally. [ABSTRACT FROM AUTHOR]

Emergent genomic analytic techniques in patients with cancer offer the potential to define the risk of myelo dysplastic syndrome (MDS) and acute leukemia (AL) manifesting following targeted radionuclide therapy of metastatic lymphoma, neuroendocrine tumors (NETs), and prostate cancer. Characterization of the genetic profile will allow risk stratification of patients before theranostic radionuclide management of advanced cancers and offers the opportunity to minimize toxicity while preserving optimal individualized efficacy in the practice of personalized precision nuclear oncology. Our review of a single-center experience of prospective radionuclide theranostic management of metastatic non-Hodgkin lymphoma (NHL), NETs, and castration-resistant prostate cancer (metastatic castrate-resistant prostate cancer [mCRPC]) over the past decade, and comparison with published studies, shows that while the risk of significant myelotoxicity is generally low, at <3%, the consequences in the small minority of patients who develop MDS or AL are substantial, and survival is poor. Timely identification of patients at heightened risk of hematologic toxic complication, using novel genomic technology before institution of radionuclide therapy, will facilitate amelioration of myelotoxicity. In current clinical practice, the minimal hematological toxicity of chemo-free theranostic management of advanced cancer is significantly less compared with newly adopted chemotherapy -immunotherapy regimens, and the financial toxicity associated with these novel agents is avoided. [ABSTRACT FROM AUTHOR]

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumors, and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumor such as prostate cancer requires the expansion of existing and the establishment of new theranostics centers. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostic centers. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)