Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with ⁶⁸Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from ⁶⁸Ga- to ¹⁸F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite ⁶⁸Ge/⁶⁸Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, ¹⁸F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, ¹⁸F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging ¹⁸F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available ¹⁸F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.

Background: Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods: A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [¹⁷⁷Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [¹⁷⁷Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results: Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [¹⁷⁷Lu]Lu-PSMA I&T and five (9.1%) for [¹⁷⁷Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [¹⁷⁷Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [¹⁷⁷Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [¹⁷⁷Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion: In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.

Objectives: C-X-C motif chemokine receptor 4 (CXCR4)-targeted radioligand therapy (RLT) has already been applied to advanced blood cancers, such as multiple myeloma or diffuse large B-cell lymphoma. We herein present a series of patients with advanced T-cell lymphoma (TCL), who were scheduled for CXCR4-directed therapy as conditioning regimen, followed by hematopoietic stem cell transplantation (HSCT). Methods: Four patients with advanced, heavily pretreated and relapsed TCL (2 males, 2 females; median age, 50 years) without suitable alternative therapeutic options underwent CXCR4-directed PET and pretherapeutic dosimetry. We then conducted CXCR4-targeted RLT in combination with allogeneic (3/4, 75%) or autologous (1/4, 25%) HSCT. One patient also underwent radioimmunotherapy targeting CD66 to enhance therapeutic efficacy. We investigated safety, best response, progression-free (PFS) and overall survival. Results: Pretherapeutic dosimetry indicated lymphoma absorbed doses of up to 33.2 Gy from CXCR4-targeted RLT. Except for one patient developing tumor lysis syndrome along with transient grade 3 kidney failure, no acute toxicity, allergic reactions or other adverse events were recorded during therapy. One patient developed septicemia and subsequently died 16 days after RLT, while engraftment was achieved in the remaining 3 subjects (75%). During follow-up, partial response was recorded in 1 patient (33.3%) and complete metabolic response in 2/3 (66.7%, with one patient also receiving additional radioimmunotherapy). Median PFS was 7 months (range, 4 – 25 m). After a median follow-up of 54 m (range, 4 – 56 m), three patients were still alive at date of censoring. Conclusion: For advanced, heavily pretreated TCL, CXCR4-directed RLT may serve as an effective conditioning therapy prior to HSCT and can cause substantial anti-lymphoma activity, leading to remarkable response in selected cases.

Purpose: We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)–directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI). Patients and Methods: Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and ⁶⁸Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and ⁶⁸Ga-FAPI-04 PET/CT. Results: Compared with GCI, ⁶⁸Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%). Conclusions: In patients affected with digestive system tumors, ⁶⁸Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer ⁶⁸Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard ¹⁸F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent ¹⁸F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. ⁶⁸Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while¹⁸F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, ¹⁸F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher ¹⁸F-FDG uptake as compared to ⁶⁸Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUV_max: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUV_mean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard ¹⁸F-FDG PET/CT.