‌Purpose‌ This phase I, first-in-human study evaluated the safety, dosimetry, and preliminary efficacy of ¹⁷⁷Lu-FAPI-XT, a novel fibroblast activation protein (FAP)-targeted radioligand, in patients with advanced solid tumors refractory to standard therapies. ‌Methods‌ This open-label, non-randomized, dose-escalation, investigator-initiated trial had a “accelerated titration” and “3 + 3” design involved a 6-week ¹⁷⁷Lu-FAPI-XT treatment cycle in patients with advanced-stage solid tumors at 3.7GBq initially, with subsequent cohorts receiving an incremental 1.85GBq dose increase until dose limiting toxicity (DLT) was observed. ‌Results‌ ¹⁷⁷Lu-FAPI-XT was well tolerated and no DLT or grade ≥ 3 treatment-related adverse events (TRAE) were observed. The whole-body effective dose was 0.039 ± 0.013 Sv/GBq. The mean effective half-lives for the whole-body and tumor lesions were 52.13 ± 12.33 h and 31.78 ± 15.03 h, respectively. According to RECIST stable disease (SD) were observed in 5 (5/14, 35.7%) patients, with the highest benefit observed in fibroblastic sarcoma subtypes with SD presented in 4 (4/8, 50%) patients. The median progression-free survival (PFS) was 4.63 m (95%CI: 1.25, NE). Metabolic reductions on PET/CT were observed in 2 sarcoma cases. (URL: hclinicaltrials.gov. Trial registration: NCT06211647, NCT06197139. Registered 4 January 2024.) ‌conclusion‌ ¹⁷⁷Lu-FAPI-XT demonstrated a favorable safety profile, with preliminary signs of tumor response observed. Complete/partial response deficiency in ¹⁷⁷Lu-FAPI-XT therapy necessitate optimized strategies for efficacy improvement.

Purpose: With the increasing detection rate of early prostate cancer (PCa), the proportion of surgical treatment is increasing. Surgery is the most effective treatment for PCa. Precise targeting of tumors during surgery can reduce the incidence of positive surgical margins (PSMs) and preserve the neurovascular bundles (NVBs) as much as possible. The objective of this study was to synthesize a PSMA fluorescent probe (PSMA-Cy5) and verify the targeting specificity of the probe for prostate cancer, thereby providing a theoretical basis for the development of PSMA fluorescent probes for clinical application in the future. Methods: In this study, a novel water-soluble 3H-indocyanine-type bioluminescent dye-Cy5-labeled prostate-specific membrane antigen (PSMA) ligand (PSMA-Cy5) was synthesized by liquid phase synthesis. The PSMA ligand was developed based on the glutamine-urea-lysine (Glu-urea-Lys) structure. The new fluorescent probe was evaluated in vitro and in vivo, and its safety was evaluated. Confocal microscopy was used to observe the binding uptake of PSMA-Cy5 with PSMA (+) LNCaP cells, PSMA (-) PC3 cells and blocked LNCaP cells. In in vivo optical imaging studies, the targeting specificity of PSMA (+) 22Rv1 tumors to probe binding was validated by tail vein injection of PSMA-Cy5. The safety of the PSMA-Cy5 probe was evaluated by histopathological analysis of mouse organs by a single high-dose tail vein injection of PSMA-Cy5. Results: In vitro fluorescence cell uptake experiments showed that the binding of PSMA-Cy5 to LNCaP cells has targeting specificity. PC3 cells and blocked LNCaP cells showed almost no uptake. The results of in vivo optical imaging studies showed that the tumor-to-background ratio in the 22Rv1 group was 3.39 ± 0.47; in the 22Rv1 blocking group it was 0.78 ± 0.15, and in the PC3 group it was 0.94 ± 0.09, consistent with the in vitro results. After a high-dose injection of PSMA-Cy5, there were no abnormalities in the tissues or organs of the mice. The probe showed good safety. Conclusions: PSMA-Cy5 is a probe with good targeting specificity and low toxicity that can accurately visualize tumors in vivo. This study has an important reference value for the development of PSMA fluorescent probes. In the future, it can be applied to precise tumor imaging during radical prostatectomy to reduce the incidence of postoperative PSM.

Prostate cancer (PCa) is a leading cause of cancer deaths, making effective early detection, precise staging, and monitoring of biochemical recurrence crucial. Next-generation prostate-specific membrane antigen (PSMA) PET tracers could detect small or early metastatic lesion, especially in patients with low prostate-specific antigen. However, species differences in PSMA expression affect tracer biodistribution and imaging performance, highlighting the need for cross-species studies to optimize design and ensure clinical accuracy. Methods: We developed [¹⁸F]Di-PyL, a dimeric, PSMA-targeted radiotracer based on the structure of [¹⁸F]DCFPyL, and systematically evaluated the biodistribution of [¹⁸F]Di-PyL in mice, pigs, dogs, and cynomolgus monkeys before conducting a preliminary imaging study in humans. The aim of these comparative analyses was to provide critical insights into the interspecies biodistribution and imaging performance of this dimeric agent, while highlighting its potential to improve the detection of PCa, particularly in patients with low prostate-specific antigen levels and biochemical recurrence. Results: [¹⁸F]Di-PyL showed a 23-fold higher PSMA-binding affinity than did [¹⁸F]DCFPyL. In vitro assays showed increased cellular uptake of [¹⁸F]Di-PyL in PSMA-positive cells. Biodistribution studies revealed significant interspecies differences, with the kidneys showing the highest uptake across all species. Distinct uptake patterns were observed in the lungs and hearts of beagles and pigs, whereas cynomolgus monkeys exhibited high uptake in salivary glands and vertebrae. In humans, significant uptake was noted in the liver and spleen. PET/CT imaging in patients with PCa revealed strong tumor localization and excellent contrast in bone metastases. Conclusion: [¹⁸F]Di-PyL is a promising PSMA PET tracer with enhanced binding affinity and excellent performance in vitro and in vivo. [¹⁸F]Di-PyL PET studies across species revealed significant biodistribution variability but consistently highlighted the tracer's superior PSMA-targeting capability. These findings provide critical data to support further preclinical animal studies and lay a solid foundation for subsequent clinical trials.

Prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals have become some of the most promising tools for the diagnosis and therapy prostate cancer (PCa). The structure of existing PSMA-targeted PET tracers still needs to be optimized to improve their pharmacokinetic properties and tumor-to-background ratio. In this study, we modified the structure of a well-studied PSMA tracer, and six novel tracers with variable hydrophilicity and pharmacokinetics were developed and evaluated both in vitro and in vivo. All of the novel tracers showed high hydrophilicity (log p = −2.99 ± 0.33 to −3.49 ± 0.01), rapid clearance rates (elimination half-times = 15.55 to 35.97 min), and high affinity for PSMA (Ki = 8.11 ± 0.49 to 42.40 ± 2.11 nM) in vitro. Specific cell binding and micro-PET experiments showed that [⁶⁸Ga]Ga-PSMA-Q displayed the highest specific PSMA+ cell uptake (3.75 ± 0.35 IA%/10⁶ at 60 min), tumor uptake (SUVmax = 0.97 ± 0.24 at 60 min p.i.), and tumor-to-muscle ratio (59.33 ± 5.72 at 60 min p.i.), while the tumor-to-muscle ratio was much higher than that of [⁶⁸Ga]Ga-PSMA-617. The results of this study validate the clinical potential of [⁶⁸Ga]Ga-PSMA-Q for PET imaging and further targeted therapy of prostate cancer.

Purpose: Prostate cancer (PCa) is characterized by high expression of prostate-specific 1membrane antigen (PSMA), a type II transmembrane protein. Prostate-specific membrane antigen positron emission tomography (PSMA PET) has high sensitivity and specificity and can therefore be potentially used to detect PCa. Exploiting the advantages of PSMA PET imaging, in this study, we aim to develop a novel radiopharmaceutical to facilitate biopsy punching of PCa. Methods: We synthesized a high-affinity radiopharmaceutical of PSMA (¹²⁵I-PSMA-7). We evaluated the properties of ¹²⁵I-PSMA-7, including the purity, stability, affinity, partition coefficient, and toxicity. (PSMA+) 22Rv1 and (PSMA−) PC3 cell lines were used to evaluate ¹²⁵I-PSMA-7 in vitro. BALB/c nude mice bearing 22Rv1 and PC3 xenografts were used for biodistribution and imaging. The uptake of the main organs was evaluated in vivo using single photon emission computed tomography (SPECT). Results: ¹²⁵I-PSMA-7 had a purity of 99.6% and remained stable for seven days and was therefore always safe to use. ¹²⁵I-PSMA-7 had a Ki of 4.037 × 10⁻¹¹ and a partition coefficient of −1.80. The results of in vitro cellular experiments showed a high uptake by 22Rv1 cells (ranging from 2.88 ± 0.14 IA%/10⁶ at 5 min to 61.98 ± 3.43 IA%/10⁶ at 24 h, where the internalization was 46.1% at 1 h and 88.06% at 24 h). However, the uptake of PC3 cells was very low (ranging from 0.34 ± 0.08 IA%/10⁶ at 5 min to 1.60 ± 0.15 IA%/10⁶ at 24 h). The tumors’ uptake of ¹²⁵I-PSMA-7 ranged from 9.02 ± 0.30 ID%/g at 1 h to 4.11 ± 1.04 ID%/g at 7 d and the tumor/muscle ratios and tumor/blood ratios increased over time. In addition, we used γ-counter to measure cpm per milligram of tumor and muscle on days 4 and 7. The background on day 4 is 42 cpm and the tumor is 1739 cpm/mg and the muscle is 45 cpm/mg, and the background on day 7 is 74 cpm and the tumor is 1404cpm/mg and the muscle is 32 cpm/mg. At 1 h post-injection, the high uptake of ¹²⁵I-PSMA-7 resulted in clear delineation of 22Rv1-derived tumors upon imaging. By comparison, 22Rv1-blocking mice took up less ¹²⁵I-PSMA-7. Conclusions: These results show that ¹²⁵I-PSMA-7 is a promising radiotracer that could be used to puncture the prostate. ¹²⁵I-PSMA-7 could be applied to targeted biopsy, reducing the need for saturated biopsy.