Background: Recent reports of the remarkable therapeutic efficacy of 225Ac-labeled PSMA- 617 for therapy of metastatic castration-resistant prostate cancer have underlined the clinical potential of targeted alpha therapy. Objective and Conclusion: This review describes methods for the production of 225Ac and its daughter nuclide 213Bi and summarizes the current clinical experience with both alpha emitters with particular focus on recent studies of targeted alpha therapy of bladder cancer, brain tumors, neuroendocrine tumors and prostate cancer.

Background: A remarkable therapeutic efficacy has been demonstrated with ²²⁵Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with ²²⁵Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma. Methods: Seventeen patients with advanced prostate cancer were selected for treatment with ²²⁵Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. ⁶⁸Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects. Results: Good antitumor activity assessed by serum PSA level and ⁶⁸Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of ²²⁵Ac-PSMA-617. Fifteen of 17 patients had a > 50% decline in lesions avidity for tracer on ⁶⁸Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation. Conclusions: ²²⁵Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

Purpose: FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of ⁶⁸Ga-FAPI versus standard-of-care ¹⁸F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers. Material and Methods: This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both ⁶⁸Ga-FAPI and ¹⁸F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ). Results: A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. ⁶⁸Ga-FAPI uptake in primary tumors and metastases was comparable to ¹⁸F-FDG in most cases. The SUVmax was significantly lower for ⁶⁸Ga-FAPI than ¹⁸F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, ⁶⁸Ga-FAPI TBRs were significantly higher than ¹⁸F-FDG TBRs in some sites, including liver and bone metastases. Conclusion: Quantitative tumor uptake is comparable between ⁶⁸Ga-FAPI and ¹⁸F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for ⁶⁸Ga-FAPI. Thus, ⁶⁸Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological ¹⁸F-FDG uptake.

Antimicrobial peptides (AMPs) are a heterogeneous class of compounds found in a variety of organisms including humans and, so far, hundreds of these structures have been isolated and characterised. They can be described as natural microbicide, selectively cytotoxic to bacteria, whilst showing minimal cytotoxicity towards the mammalian cells of the host organism. They act by their relatively strong electrostatic attraction to the negatively charged bacterial cells and a relatively weak interaction to the eukaryote host cells. The ability of these peptides to accumulate at sites of infection combined with the minimal host’s cytotoxicity motivated for this review to highlight the role and the usefulness of AMPs for PET with emphasis on their mechanism of action and the different interactions with the bacterial cell. These details are key information for their selective properties. We also describe the strategy, design, and utilization of these peptides as potential radiopharmaceuticals as their combination with nuclear medicine modalities such as SPECT or PET would allow noninvasive whole-body examination for detection of occult infection causing, for example, fever of unknown origin.

Background: Metastatic prostate carcinoma over-expresses the prostate specific membrane antigen (PSMA) making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience in a series of 73 castrate resistant prostate carcinoma patients treated with ²²⁵Ac-PSMA-617, identifying variables predictive for overall and progression free survival following ²²⁵Ac-PSMA-617 treatment. Methods: ²²⁵Ac-PSMA-617 was administered to patients with mCRPC who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. ⁶⁸Ga-PSMA PET/CT was obtained at baseline, prior to every treatment cycle and on follow-up for patients’ selection for treatment, to determine the activity of treatment agent to be adminsitered and for response assessment. Serial (prostate specific antigen) PSA was obatianed for PSA response assessment. Results: Seventy-three men (mean age=69 years, range:45-85) with mCRPC were treated with 210 cycles of ²²⁵Ac-PSMA-617. In 70% of patients, a PSA decline of ≥50% was obtained while 83% of patients had any PSA decline. In 29% of patients, all lesions on ⁶⁸Ga-PSMA-PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression while 13 patients died from their disease. The estimated median progression free survival (PFS) and overall survival (OS) were 15.2 months (95% CI: 13.1 – 17.4) and 18 months (95% CI: 16.2 – 19.9) respectively. On univariate analyses factors such as baseline PSA, any PSA decline, PSA decline ≥50%, prior chemotherapy, prior radiation therapy, baseline hemoglobin level were associated with longer PFS and OS (all p 50% proved significantly associated with OS and PFS in multivariate analysis following treatment with ²²⁵Ac-PSMA-617. Furthermore, previous ¹⁷⁷Lu-PSMA treatment was negatively associated with PFS in both uni- and multivariate analysis.