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Due to the heterogeneity of tumors, strategies to improve the effectiveness of dual-targeting tracers in tumor diagnostics have been intensively practiced. In this study, the radiolabeled [18F]AlF-NOTA-FAPI-RGD (denoted as [18F]AlF-LNC1007), a dual-targeting heterodimer tracer targeting both fibroblast activation protein (FAP) and integrin αvβ3 to enhance specific tumor uptake and retention, was synthesized and evaluated. The tracer was compared with [68Ga]Ga-LNC1007 in preclinical and clinical settings. Methods: The preparation of [18F]AlF- and 68Ga-labeled FAPI-RGD was carried out with an optimized protocol. The stability was tested in PBS and fetal bovine serum (FBS). Cellular uptake and in vivo distribution of the two products were compared and carried out on the U87MG cell line and its xenograft model. The safety and dosimetry of [18F]AlF-LNC1007 PET/CT scan were evaluated in six patients with malignant tumors. Results: Two radiolabeling protocols of [18F]AlF-/[68Ga]Ga-LNC1007 were developed and optimized to give a high yield of tracers with good stability. In vivo microPET images showed that the two tracers exhibited comparable pharmacokinetic characteristics, with high tumor uptake and prolonged tumor retention. In vivo distribution data showed that the target-to-non-target ratios of [18F]AlF-LNC1007 were similar to[68Ga]Ga-LNC1007. A total of six patients underwent [18F]AlF-LNC1007 PET/CT evaluation while two had head-to-head [18F]FDG PET/CT scans. The total body effective dose was 9.94E-03 mSv/MBq. The biodistribution curve showed optimal normal organ uptake with high tumor uptake and long retention of up to 3h p.i., and notably, the tumor-to-background ratio increased over time. Conclusion: We successfully prepared an [18F]AlF-LNC1007 dual-targeting PET probe with comparable performances as [68Ga]Ga-LNC1007. With prolonged tumor retention and tumor specificity, it produced good imaging quality in preclinical and clinical translational studies, indicating that [18F]AlF-LNC1007 is a promising non-invasive tracer for detecting tumors expressing FAP and/or integrin avβ3, with the prospect of clinical implementation. [ABSTRACT FROM AUTHOR]

Purpose: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of 177Lu-PSMA-EB-01 (denoted as [177Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [177Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval. Results: Patients received fractionated doses of [177Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for 177Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle. Conclusion: This phase 1 trial revealed that the MTD of [177Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [177Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [177Lu]Lu-LNC1003 treatment. Trial registration: 177Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registryhttps://classic.clinicaltrials.gov/ct2/show/NCT05613738 [ABSTRACT FROM AUTHOR]