From Automated Synthesis to In Vivo Application in Multiple Types of Cancer—Clinical Results with [68Ga]Ga-DATA5m.SA.FAPi

Abstract

Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in regions with high glucose metabolism, no need for fasting, and rapid imaging). In this study, we wanted to evaluate the radiochemical synthesis and the clinical properties of the new CAF-targeting tracer [68Ga]Ga-DATA5m.SA.FAPi. The compound consists of a (radio)chemically easy to use hybrid chelate DATA.SA, which can be labeled at low temperatures, making it an interesting molecule for ‘instant kit-type’ labeling, and a squaric acid moiety that provides distinct advantages for synthesis and radiolabeling. Our work demonstrates that automatic synthesis of the FAP inhibitor [68Ga]Ga-DATA5m.SA.FAPi is feasible and reproducible, providing convenient access to this new hybrid chelator-based tracer. Our studies demonstrated the diagnostic usability of [68Ga]Ga-DATA5m.SA.FAPi for the unambiguous detection of cancer-associated fibroblasts of various carcinomas and their metastases (NSCLC, liposarcoma, parotid tumors, prostate cancer, and pancreas adenocarcinoma), while physiological uptake in brain, liver, intestine, bone, and lungs was very low.

Preliminary Findings of the Role of FAPi in Prostate Cancer Theranostics

“…A recent study by Greifenstein et al [ 13 ] assessed the “kit-type” synthesis of the CAF-targeting tracer [ 68 Ga]Ga-DATA5m.SA.FAPi and analysed the tracer’s uptake and biodistribution in one patient with sarcoidosis and five patients with various histologically confirmed metastatic malignancies, including one patient with PCa. With a very low physiological uptake in the brain, liver, intestine, bone and lungs, [ 68 Ga]Ga-DATA5m.SA.FAPi showed a biodistribution similar to that of FAPi-02, but with less kidney uptake and blood pool activity and a higher uptake of [ 68 Ga]Ga-DATA5m.SA.FAPi than FAPI-46 and FAPi-74 in the malignant lesions.…”

“…However, in over 90% of the most common human epithelial tumours, it is overexpressed in the stroma and is histologically characterised by desmoplastic reactions [ 12 ]. FAP overexpression increases the risk of tumour invasion, lymph node metastasis and the decreased overall survival (OS) [ 12 , 13 , 14 , 15 ] of many solid cancers, including mCRPCa [ 16 ], especially if the cancer exhibits neuroendocrine (NE) differentiation [ 17 ]. It thus represents a potential target for theranostics applications for aggressive (and often, low-PSMA-expressing) PCa [ 13 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

“…FAP overexpression increases the risk of tumour invasion, lymph node metastasis and the decreased overall survival (OS) [ 12 , 13 , 14 , 15 ] of many solid cancers, including mCRPCa [ 16 ], especially if the cancer exhibits neuroendocrine (NE) differentiation [ 17 ]. It thus represents a potential target for theranostics applications for aggressive (and often, low-PSMA-expressing) PCa [ 13 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. In this systematic review, we provide an overview of clinical applications using FAPi ligands in the PCa theranostics scenario by summarising the main preliminary results.…”

Druglike, 18F-labeled PET Tracers Targeting Fibroblast Activation Protein

“…The title compound was obtained by eluting with 5−50% EtOAc/nheptane and obtained as a white solid (31% yield). (27). A 10 mL cylindrical flask was charged with methyl 6-(((trans)-2,2-dimethyl-5-((tosyloxy)methyl)-1,3-dioxolan-4-yl)methoxy)quinoline-4-carboxylate (0.24 g, 0.479 mmol) and 5 mL of dry MeOH.…”

[111In]In/[177Lu]Lu-AAZTA5-LM4 SST2R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results

“…An alternative route to overcome this problem is the introduction of hybrid chelators which allow fast coordination of the radiometal at lower temperatures without compromising the stability of the forming radiometal chelate [ 23 , 24 ]. Thus, the bifunctional hybrid chelator DATA 5m ((6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate) has been coupled to a variety of interesting vectors, including SST 2 R-targeting peptide motifs, enabling the facile and stable coordination of radiogallium (Ga-67/68) [ 25 , 26 , 27 , 28 , 29 ]. Preclinical studies have acquired convincing evidence for the successful clinical application of resulting [ 68 Ga]Ga-radioligands with PET/CT.…”