BACKGROUND: [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) is recommended during diagnostic work-up for ovarian cancer; however, [18F]FDG PET has several inherent limitations. The novel oncologic PET-tracer fibroblast activation protein inhibitor (FAPI) has demonstrated promising results in multiple cancer types, including ovarian cancer, and could overcome the limitations of [18F]FDG PET; however, high-quality clinical studies are lacking. The primary objective of the present study is to compare the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT and [18F]FDG PET/CT in ovarian cancer patients and to investigate how this potential difference impacts staging and patient management.
METHODS: Fifty consecutive ovarian cancer patients will be recruited from Aalborg University Hospital, Denmark. This study will be a single-center, prospective, exploratory clinical trial that adheres to the standards for reporting diagnostic accuracy studies (STARD). This study will be conducted under continuous Good Clinical Practice monitoring. The eligibility criteria for patients are as follows: (1) biopsy verified newly diagnosed ovarian cancer or a high risk of ovarian cancer and referred for primary staging with [18F]FDG PET/CT; and (2) resectable disease, i.e., candidate for primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery. All recruited study subjects will undergo [68Ga]Ga-FAPI-46 PET/CT at primary staging, before primary debulking surgery or neoadjuvant chemotherapy (Group A + B), in addition to conventional imaging (including [18F]FDG PET/CT). Study subjects in Group B will undergo an additional [68Ga]Ga-FAPI-46 PET/CT following neoadjuvant chemotherapy prior to interval debulking surgery. The results of the study-related [68Ga]Ga-FAPI-46 PET/CTs will be blinded, and treatment allocation will be based on common clinical practice in accordance with current guidelines. The histopathology of surgical specimens will serve as a reference standard. A recruitment period of 2 years is estimated; the trial is currently recruiting.
CONCLUSIONS: To our knowledge, this trial represents the largest, most extensive, and most meticulous prospective FAPI PET study conducted in patients with ovarian cancer thus far. This study aims to obtain a reliable estimation of the diagnostic accuracy of [68Ga]Ga-FAPI-46 PET/CT, shed light on the clinical importance of [68Ga]Ga-FAPI-46 PET/CT, and examine the potential applicability of [68Ga]Ga-FAPI-46 PET/CT for evaluating chemotherapy response.
BACKGROUND: clinicaltrials.gov: NCT05903807, 2nd June 2023; and euclinicaltrials.eu EU CT Number: 2023-505938-98-00, authorized 11th September 2023.

BACKGROUND: The demand for 68Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, 68Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([68Ga]Ga-FAPI-46) in late-phase studies, whereas [68Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.
RESULTS: Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [68Ga]Ga-FAPI-46 and 46 ± 7% for [68Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including 68Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.
CONCLUSIONS: The microfluidic-based approach enabled the implementation of radiosynthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2-3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [68Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.

[68Ga]Ga-FAPI-46 is a radiolabelled fibroblast activation protein inhibitor that selectively binds to fibroblast activation protein (FAP), which is overexpressed by cancer-associated fibroblasts (CAFs) in the tumour microenvironment. In recent years, radiolabelled FAP inhibitors (FAPIs) are becoming increasingly important in cancer diagnostics and also for targeted radionuclide therapy. Because of the increasing demand for radiolabelled FAPIs, automating the synthesis of these compounds is of great interest. In this work, we present a newly programmed automatic synthesis process of [68Ga]Ga-FAPI-46 on a Scintomics GRP module using two Galli Ad generators as a radionuclide source. Dedicated cassettes for the labelling of 68Ga-peptides were used without any modifications. The generators were connected via a three-way valve to the module and eluted automatically over a strong cation exchange (SCX) cartridge by using the vacuum pump of the synthesis module, eliminating the need to transfer the eluates into a separate vial. After a reaction step in HEPES buffer, the compound was purified by solid-phase extraction (SPE) over a Sep-Pak Light C18 cartridge. The evaluation of 10 routine syntheses of [68Ga]Ga-FAPI-46 resulted in a radiochemical yield of 72.6 ± 4.9%. The radiochemical purity was 97.6 ± 0.3%, and the amount of free gallium-68 and colloid was <2%. The final product fulfilled the quality criteria, which were adapted from relevant monographs of the European Pharmacopoeia (Ph. Eur.). This work presents the successful preparation of multiple doses of [68Ga]Ga-FAPI-46 in a GMP-compliant automated process for clinical use.