Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells’ DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β– emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225Ac-PRRT in NETs, discuss the strengths and challenges of 225Ac complexes being used in PRRT; and envision the prospect of 225Ac-PRRT as a future alternative in the treatment of NETs.

Rationale: Early discovery, accurate diagnosis, and staging of lung cancer is essential for patients to receive appropriate treatment. PET/CT has become increasingly recognized as a valuable imaging modality for these patients, but there remains room for improvement in PET tracers. We aimed to evaluate the feasibility of using [ 68 Ga]Ga-FAPI-RGD, a dual-targeting heterodimeric PET tracer that recognizes both fibroblast activation protein (FAP) and integrin α v β 3 for detecting lung neoplasms, by comparing it with [ 18 F]FDG and single-targeting tracers [ 68 Ga]Ga-RGD and [ 68 Ga]Ga-FAPI. Methods: This was a pilot exploratory study of patients with suspected lung malignancies. All 51 participants underwent [ 68 Ga]Ga-FAPI-RGD PET/CT, of which: 9 participants received dynamic scans, 44 participants also underwent [ 18 F]FDG PET/CT scan within two weeks, 9 participants underwent [ 68 Ga]Ga-FAPI PET/CT scan and 10 participants underwent [ 68 Ga]Ga-RGD PET/CT scan. The final diagnosis was made based on histopathological analyses and clinical follow-up reports. Results: Among those who underwent dynamic scans, the uptake of pulmonary lesions increased over time. The optimal timepoint for a PET/CT scan was identified to be 2 h post-injection. [ 68 Ga]Ga-FAPI-RGD had a higher detection rate of primary lesions than [ 18 F]FDG (91.4% vs. 77.1%, p < 0.05), higher tumor uptake (SUVmax, 6.9 ± 5.3 vs. 5.3 ± 5.4, p < 0.001) and higher tumor-to-background ratio (10.0 ± 8.4 vs. 9.0 ± 9.1, p < 0.05), demonstrated better accuracy in mediastinal lymph node evaluation (99.7% vs. 90.9%, p < 0.001), and identified more metastases (254 vs. 220). There was also a significant difference between the uptake of [ 68 Ga]Ga-FAPI-RGD and [ 68 Ga]Ga-RGD of primary lesions (SUVmax, 5.8 ± 4.4 vs. 2.3 ± 1.3, p < 0.001). Conclusion: In our small scale cohort study, [ 68 Ga]Ga-FAPI-RGD PET/CT gave a higher primary tumor detection rate, higher tracer uptake, and improved detection of metastases compared with [ 18 F]FDG PET/CT, and [ 68 Ga]Ga-FAPI-RGD also had advantages over [ 68 Ga]Ga-RGD and was non-inferior to [ 68 Ga]Ga-FAPI. We thus provide proof-of-concept for using [ 68 Ga]Ga-FAPI-RGD PET/CT for diagnosing lung cancer. With the stated advantages, the dua...