# The Role of PET and SPECT Imaging in Prostate Cancer Targeted Alpha Therapy: When and How?
## 5 \({}^{225}\)Ac/\({}^{213}\)Bi-PSMA TAT
It has already been shown in patients with neuroendocrine tumors that beta-resistance to \({}^{90}Y/^{177}\)Lu-DOTATOC can be overcome by alpha-emitting Bi-DOTATOC [73]. The primary pharmacokinetic characteristics of PSMA-617, the main substance in the literature overview, such as its rapid clearance of unbound ligand, high internalization rate, prolonged tumor retention, and fast tumor uptake are highly advantageous for combination with an alpha emitter with a half-life of several days [74]. The estimated Dosimetry of \({}^{213}\)Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application [75], which was evaluated in favorable pre-clinical papers [76]. No clinical studies demonstrating the efficacy and safety of Bi-J591 in the treatment of mCRPC have been reported yet, but the first-in-human treatment concept with 213 Bi-PSMA-617 in a patient with mCRPC that was progressive under conventional therapy showed a remarkable molecular imaging and biochemical response [77]. Nevertheless, according to a previous paper, compared to \({}^{225}\)Ac-PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of \({}^{213}\)Bi, rendering this nuclide as a second-choice radiolabel for targeted alpha therapy of prostate cancer [75]. Therefore, ongoing studies are mainly focused on \({}^{225}\)Ac rather than \({}^{213}\)Bi. An overview of ongoing studies focused on PSMA-based TAT registered on Clinicaltrials.org is provided in Table 1. Nevertheless, without comparative trials, there is no proof of whether, applied in identical clinical situations, \({}^{225}\)Ac-PSMA-617 is more efficient than Lu-PSMA-617 or vice versa. However, there is some good rationale that PSMA-based TAT might have advantages in specific clinical indications [62], such as in 177 Lu non-responding cancers. \({}^{225}\)Ac-PSMA-617/\({}^{177}\)Lu-PSMA-617 tandem therapy was reported as an effective treatment option in patients who exhibited progress or an insufficient response to \({}^{177}\)Lu-PSMA-617 monotherapy [78; 79; 80] with low treatment-related toxicities [79; 81]. Formal study of this combination is warranted. Molecular imaging response and biochemical PSA response were mostly concordant, but molecular imaging response reflecting the change in total viable tumor burden appears to be superior to PSA change in estimating survival outcome after \({}^{225}\)Ac-PSMA-617/\({}^{177}\)Lu-PSMA-617 tandem therapy [78]. The typical candidate for TAT with \({}^{225}\)Ac-PSMA will have prostate cancer that has been histologically proven, is castration-resistant, and has progressed in standard therapy. The choice to administer \({}^{225}\)Ac-PSMA to a patient should be decided in a multidisciplinary environment [68]. Based on the known toxicity of \({}^{225}\)Ac-PSMA therapy,a special focus on bone marrow and kidneys functionalities should be considered in the patient's selection. The growing scientific data will improve the selection's criteria for TAT, but according to a recent comprehensive review [68], an acceptable organ reserve commonly applied in routine clinical practice includes:  
* Bone marrow function: hemoglobin level >8 g/dL; platelet count >75 \(\times\) 10/L, white cell count >3 \(\times\) 10/L;
* Renal function: serum creatinine <2\(\times\) the upper limit of normal.