Project Summary/Abstract: Targeted alpha (α) therapy (TAT) has emerged as an attractive approach to a range of cancers due its ability to target cancer cells while minimizing nominal tissue toxicity. Of the various TAT approaches currently under development, peptide-based targeting strategies offer high receptor affinity and selectivity, coupled with more rapid pharmacokinetics than other longer-lived targeting strategies, such as antibody-based targeting. These shorter-lived but target-selective strategies require α-emitting nuclides with half-lives on the order of hours. This allows reasonable labelling time, while limiting the loss of isotope through rapid degradation of the targeting molecule. Of the possible α-emitters for this purpose, 212Pb (t1/2 10.6 h) is best-suited. In addition to appropriate decay kinetics, 212Pb has the advantage of a clear path to theranostic TAT through a partner radionuclide (203Pb), which exhibits slow gamma-decay well-suited to diagnostic imaging for patient-specific treatment stratification and dosing. However, the development of 212Pb-based TATs is hindered by limited 212Pb supply. Thus far, no supplier has emerged to meet the increasing clinical demand for 212Pb that will prevent advancement of candidate 212Pb therapies beyond early-phase clinical trials. Radtran LLC has designed and patent-protected a highly selective, high-yield, simple, and environmentally conscious process for collecting 224Ra, which is the generator feedstock for 212Pb. This process also has potential to disrupt the production paradigm for many similar medically attractive radioisotopes including 225Ac and 223Ra. The feedstock material for 224Ra generation is natural thorium (232Th); a byproduct of many mining operations. Natural thorium is readily available from large aboveground stockpiles, including that belonging to Solvay, with whom RadTran has established an ongoing supply agreement. Radtran's partner, Viewpoint Molecular Targeting Inc., (Viewpoint) has secured rights to two 212Pb generators being developed as well as a theranostic treatment targeting metastatic melanoma through conjugation of 203Pb and 212Pb to a novel peptide targeting the melancortin-1 receptor. Coupling the two company's technologies provides an avenue for creating a full-value-chain enterprise for 212Pb generation. This Phase 1 proposal seeks to determine the feasibility of coupling RadTran's 224Ra feedstock isolation approach with the two 212Pb generator technologies under investigation by Viewpoint. RadTran intends to advance the technology to the Phase II development stage by completing a single specific aim. That aim is to demonstrate feasibility of extracting radium (in the form of 224Ra and 228Ra) from 232Th, loading that radium into solid phase generators of 212Pb, and incorporating the delivered 212Pb into a clinically relevant cancer-targeting peptide. Separation efficiencies, separation purities, and conjugation efficiencies will be investigated t...