# The Role of PET and SPECT Imaging in Prostate Cancer Targeted Alpha Therapy: When and How?
### Nuclear Medicine Therapy and Prostate Cancer: What Is Known  
For the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have already had androgen receptor (AR) pathway inhibition and taxane-based chemotherapy, the FDA has authorized PLUVICTOTM (Lutetium 177 Lu vipivotide [14]. Additionally, the FDA has authorized the use of Locametz(r) (East Hanover, NJ, USA) (gallium 68 Ga gozetotide), a diagnostic imaging agent, to detect PSMA-positivelesions using positron emission tomography (PET). In this perspective, the two radiopharmaceuticals are employed according to the so-called theranostic approach, consisting of the sequential administration of two molecules with identical or very similar characteristics: the first one is bound to a radionuclide emitting photons or positrons for diagnostic purposes, while the second is conjugated with a radionuclide emitting particles to exert an anti-tumor effect, as shown in Figure 1[15]. Targeted alpha therapy (TAT) represents an optimal weapon against cancer cells because it can selectively deliver a high burden of radiation to cancer cells and spares normal surrounding tissue thanks to the short range of alpha particles [16; 17]. The great energy deposition results in the possibility of obtaining irreparable damage in DNA which is oxygen independent and hence eliminates the major mechanism of therapeutic resistance [18]. In the landscape of targeted alpha therapy, Radium-223 (\({}^{223}\)Ra) is a cornerstone. The double-stranded DNA breaks caused by this alpha emitter in cancer cells are incorporated into osteoblastic metastatic lesions. For mCRPC patients with symptomatic bone metastases but no visceral metastases, the FDA authorized it in 2013 [19]. New agents have been proposed such as Thorium 227 (\({}^{227}\)Th). It has been conjugated to BAY2315497, a human anti-PSMA antibody, which demonstrated a preferential tumor uptake. The combination with AR antagonist increased the sensibility to growth inhibition. This seemed to be due to the improved PSMA expression induced by AR antagonist [20]. Actinium-225 PSMA (\({}^{225}\)Ac-PSMA), indeed, has been proposed for \"superscan\" patients because the short tissue penetration range of its alpha particle could result in a more favorable microdosimetry in case of red marrow infiltration [21]. Another alpha emitter example is Astatine-211 (\({}^{211}\)At) linked with PSMA, which was recently investigated for the treatment of PCa [18].  
Figure 1: A 59-year-old man affected by prostate cancer, diagnosed in 2016 and submitted to prostatectomy ([PERSON] score 4 + 5, ISUP 5, pT3b pN1), subsequently treated with adjuvant androgen deprivation therapy. After 2 years, progressively increasing values of PSA were registered, and the patient underwent 2 nd generation anti-androgen therapy with abiraterone and, due to progressive skeletal disease, chemotherapy with taxanes. (**A**) Whole Body \({}^{68}\)Ga-PSMA-11 PET/CT demonstrated highly increased tracer incorporation within metastases in the thorax (black bordered arrow) and pelvis (black arrow). (**B**) Fused PET/CT axial images well depicted PSMA-avid lesions in sacrum (upper row, white arrow) and in a pelvic node (lower row, white arrow). Two months later, he underwent radioligand therapy with \({}^{177}\)Lu-PSMA-617; PSMA PET/CT was not repeated due to the shortage of tracer’s availability. (**C**) Whole planar images (left side; anterior view, right side: posterior view) carried out by scintigraphy on \({}^{177}\)Lu’s photopeaks after the 1 st cycle of \({}^{177}\)Lu-PSMA-617 showed multiple sites of tracer incorporation with a much more extensive skeletal metastatization than that revealed by PET/CT. This discrepancy might be explained by the too long interval of time occurred between the diagnostic phase and the therapeutic procedure in a subject with rapidly progressive disease.