Prostate cancer (PC) is the second most common cancer and the second leading cancer-related cause of death in men. The American Cancer Society has estimated that 248,530 new cases of prostate cancer and 34,130 prostate cancer-related deaths will occur in 2021. Androgen deprivation therapy (ADT) — either chemical castration or orchiectomy — is used as an initial therapy for PCs; however, most patients develop metastatic castration-resistant PC (mCRPC). Patients with mCRPC have less than a 16% chance of surviving for five years, making better therapeutic options a critical need. Radiolabeled prostate-specific membrane antigen inhibitors (PSMAi) are being investigated for the treatment of PC patients. One such agent, labeled with the β-emitter 177Lu (177Lu-PSMA-617) is in late stage of its Phase III clinical evaluation. Although it has shown promise, dose-limiting hematological toxicity due to diffuse red marrow infiltration of its long-range β-particles is a problem. Because of their higher capability to generate DNA double strand breaks than β-particles, high linear energy transfer (LET) alpha-particles (AP) should be more effective for treating resistant tumors. Furthermore, due to their short range in tissue, they should be ideal for treatment of micrometastatic lesions. PSMAi labeled with AP-emitting 225Ac have yielded response rates significantly higher than that of 177Lu-PSMA-617 with less severe bone marrow toxicity. However, due to their predominantly nonspecific uptake in salivary and lachrymal glands, xerostomia and xerophthalmia were significant issues. Auger electrons (AE) are high LET radiation when positioned near DNA and have very short range. They can be lethal when in the tumor cell nuclei but will have minimal off-target toxicity. Poly ADP-ribose polymerase 1 (PARP1) is a DNA repair protein that is highly expressed in cancers and to a lesser degree in normal tissues. Because PARP1 localizes adjacent to DNA, we propose to develop AE emitter (AEE)-labeled covalent conjugates of PSMAi and inhibitors of PARP1 (PARPi) for the targeted AEE therapy of mCRPC patients. The hypothesis is that the PSMAi part of the conjugate can achieve specific binding to PSMA in the PC cells and, PARP-1 being a nuclear protein, the PARPi moiety will help localize AEE in the tumor cell nuclei where the AEE will be most effective. In addition to AP, the heavy halogen 211At emits high LET recoil nuclei with a mean range in tissue of 82 and 105 nm, which is highly cytotoxic when the decay occurs within the nucleus. It also emits ~6 AEs per decay, which deposits more radiation dose than its AP within 10 nm of the decay site. For these reasons, 211At-labeled analogues also should be effective with these conjugates. The Specific Aims are: 1) Syntheses of PARPi-PSMAi radioconjugates for Auger and Alpha therapy; 2) In vitro evaluation of radioconjugates; 3) In vivo biodistribution of radioconjugates. Successful completion of this project is expected to identify an ...