The global burden of breast cancer has risen markedly in recent years. In 2020, breast cancer surpassed lung cancer to become the most frequently diagnosed malignancy worldwide and persists as a primary determinant of cancer mortality in the female population [1,2]. This growing disease burden highlights the pressing requirement for more effective targeted treatment approaches.

Cellular DNA repair, especially the correction of single-strand breaks, critically depends on Poly(ADP-ribose) polymerase 1 (PARP-1). Inhibition of PARP-mediated DNA repair has emerged as a promising therapeutic strategy that can selectively induce tumor cell death through synthetic lethality [[3], [4], [5], [6]]. Clinically, PARP inhibitors (PARPis) exploit this mechanism and have demonstrated efficacy particularly in tumors with defective homologous recombination repair, such as BRCA-deficient cancers [[7], [8], [9], [10], [11], [12]]. PARPis are nicotinamide adenine dinucleotide (NAD+) analogs that competitively inhibit the catalytic domain of PARP enzymes. To date, four PARPis have been approved by the U.S. Food and Drug Administration (FDA): Olaparib (2014) [13], Rucaparib (2016) [14], Niraparib (2017) [15], and Talazoparib (2018) [16]. In 2020, the National Medical Products Administration (NMPA) of China approved Fuzuloparib, the first domestically developed PARPi, is approved for gBRCAm patients with recurrent ovarian, fallopian tube, or primary peritoneal cancers showing platinum sensitivity, following at least two prior chemotherapy regimens. [[17], [18], [19], [20]]. In 2024, Fuzuloparib was further granted breakthrough therapy designation by the NMPA for a new indication targeting human epidermal growth factor receptor 2 (HER2)-negative breast cancer with BRCA mutations [18].

Despite their clinical success, the broader application of PARPis is limited by challenges such as suboptimal biodistribution, limited specificity, and the lack of tools for real-time efficacy evaluation. In this context, non-invasive imaging techniques, especially positron emission tomography (PET), have gained traction for quantitatively assessing PARP expression in vivo, thereby enabling dynamic monitoring of tumor biology and therapeutic response [21,22]. PET imaging of PARP-targeted radiotracers provides critical insights into key pharmacokinetic parameters, including drug biodistribution, tumor uptake, metabolism, and drug-target interactions. This information is essential for informing clinical decisions related to cancer diagnosis, staging, and the personalization of therapy [[23], [24], [25], [26], [27]]. Several fluorinated PARP-targeted radiotracers, such as [18F]PARPi [23,24], and [18F]FluorThanatrace ([18F]FTT) [[25], [26], [27]], which are fluorinated derivatives designed based on the PARP inhibitor pharmacophore, as well as radiolabeled isotopologues of clinically used PARPis, including [18F]Olaparib [28], [18F]Talazoparib [29], and [18F]Rucaparib [30], have been successfully synthesized. These radiotracers retain high affinity for PARP-1, enable accurate visualization of target engagement, and serve as valuable tools for patient stratification, therapeutic monitoring, and assessing combination regimens with chemotherapy or immunotherapy. However, pharmacokinetic limitations such as unfavorable tumor uptake [31,32], rapid clearance from tumor tissue [[30], [31], [32]], and low tumor-to-background contrast [[28], [29], [30],33], compromise image quality and reduce diagnostic reliability. Therefore, there is a critical need for novel PARP radiotracers with improved tumor retention, higher specificity, and superior imaging contrast to better support precision oncology.

Fuzuloparib contains a trifluoromethyl group that contributes to its pharmacological properties. The strong electron-withdrawing and steric effects of this group confer metabolic stability by reducing enzymatic degradation, while its hydrophobic nature facilitates cell membrane penetration and improves overall bioavailability [34,35]. In this study, we report the radiosynthesis and preliminary biological evaluation of [18F]Fuzuloparib. The human epidermal growth factor receptor 2 (HER2)-positive and androgen receptor (AR)-positive breast cancer cell line MDA-MB-453 cell, was selected as the primary tumor model due to its high PARP-1 expression. Although MDA-MB-453 is not BRCA-mutated, its elevated PARP-1 levels make it suitable for evaluating PARP-targeted radiotracers and exploring the potential of imaging PARP-expressing tumors beyond the classical BRCA-deficient context. A549, a lung adenocarcinoma cell line with low PARP-1 expression, served as a non-breast cancer comparator, providing a negative control to assess tracer specificity and tumor uptake. Using these models, we investigated the in vivo distribution and tumor-targeting properties of [18F]Fuzuloparib, demonstrating its favorable uptake and retention, and highlighting its promise as a PET imaging agent for clinical translation.