# The Role of PET and SPECT Imaging in Prostate Cancer Targeted Alpha Therapy: When and How?
## 5 \({}^{225}\)Ac/\({}^{213}\)Bi-PSMA TAT  
Only a small number of clinical trials, early dosimetry attempts, and some retrospective observational studies have examined PSMA-targeting alpha-particle therapy (TAT) [62]. These include anti-PSMA antibodies such as J591 and PSMA targeted small molecules ligands such as MIP-1095, PSMA I and T, and PSMA-617 labeled with alpha particle-emitting isotopes [63]. Alpha emitters present several advantages for cancer therapy. Its usage in clinical practice is advised solely for patients without visceral metastases since \({}^{223}\)Ra primarily targets skeletal lesions. Multiple attempts have been made to create radiopharmaceuticals that are appropriate for TAT and focused on the biomarker PSMA, which is overexpressed by both skeletal and visceral metastases from mCRPC, in order to work around this constraint [64]. Imaging with PSMA ligands indicates the specificity  
Figure 2: A 71-year-old man affected by prostate cancer, diagnosed in 2009 and submitted to prostatectomy ([PERSON] score 4 + 3, ISUP 3, pT2 pN0). After 8 years, progressively increasing values of PSA were registered, and the patient underwent a sequence of therapeutic regimens (antiandrogen deprivation therapy, 2 nd generation antiandrogen therapy with enzalutamide, chemotherapy with taxanes). In 2022, due to progressive disease at a skeletal level, he was submitted to PET/CT with \({}^{18}\)F-choline and \({}^{68}\)Ga-PSMA-11 before enrollment for \({}^{223}\)Ra-therapy. (**A**) Whole body (left side) and fused sagittal \({}^{18}\)F-choline PET/CT (right side) demonstrated highly increased tracer incorporation in the thoracic spine (white bordered arrows). (**B**) Whole body (left side) and fused sagittal \({}^{68}\)Ga-PSMA-11-PET/CT (right side) depicted multiple PSMA-avid lesions in the cervical, thorax and lumbar spine (white arrows). Note that the extension of skeletal involvement shown by \({}^{68}\)Ga-PSMA PET/CT is much more relevant with respect to that demonstrated by \({}^{18}\)F-choline. of the interaction [65]. Several PSMA small molecules (PSMA-617, PSMA I&T, MIP-1095) have been used with beta-emitters such as lutetium-177 (Lu) or iodine-131 [66]. Numerous groups from all over the world have published extensive reports on the safety and effectiveness of \({}^{177}\)Lu-PSMA for the treatment of mCRPC [66]. Despite the impressive response of mCRPC to \({}^{177}\)Lu-PSMA-617, a sizable percentage of patients may not benefit from the treatment. Ref. [67] or may demonstrate an initial response followed by a disease progression [68]. This has, therefore, led to an interest in the evaluation of the safety and efficacy of PSMA-based alpha therapy as a therapeutic alternative for mCRPC patients who may be unsuitable for or resistant to \({}^{177}\)Lu-PSMA-617. The physical limitation of \(\beta\)-particle-emitting radiopharmaceuticals as \({}^{177}\)Lu-labeled is their long energy emission range, which may lead to damages in surrounding healthy cells. Therefore, \(\beta\)-particle-emitting therapies are consequently less appropriate for smaller cancerous foci [69]. Theoretically, TAT, on the other hand, deposits energy within a few cell diameters, resulting in a less toxic treatment and a very high relative biological efficacy with an improved cytotoxic potential [70; 71]. Therefore, a growing scientific interest is focused on alpha-emitting agents such as Actinium (Ac) or Bismuth (Bi) and others that can be delivered to PSMA, expressing tumors regardless of their metastatic location [72]. In fact, PSMA-based TAT holds the promise of becoming a powerful tool for the management of mCRPC, but several issues are still a matter of debate, especially concerning TAT toxicity, TAT monitoring, and the eventual necessity of a personalized approach. Clearly, further trials focused on toxicity and dosimetric findings of PSMA-based TAT are needed to clarify these aspects. However, there are not many alpha emitters with sufficient half-lives between hours and days that can be used often in clinical settings.