PROJECT SUMMARY CD46 is highly expressed in multiple cancers, including both adenocarcinoma and neuroendocrine types of metastatic castration resistant prostate cancer (mCRPC). Its expression on normal tissue is generally low except for placental trophoblasts during pregnancy and to a lesser degree the prostate epithelium. An anti-CD46 antibody-drug conjugate (ADC) originally developed in the Liu lab is now in phase I trials at five US centers for mCRPC. UCSF is the leading test site (led by significant contributor Dr. Rahul Aggarwal) and the first patient has been dosed. An important challenge for this type of therapy is the appropriate selection of CD46-positive patients who will likely respond to therapy. One method to assay CD46 positivity would be through tissue sampling. However, biopsies do not reflect target expression in all lesions but rather the characteristic of a specific tumor metastatic lesion. In contrast, non-invasive molecular imaging using anti-CD46 radiotracers will allow for whole body assessment of antigen expression and consequently identification of patients who are likely to respond to this novel therapy. CD46 has been very recently discovered as a novel target of advanced prostate cancer; therefore, there is a gap in fundamental information about whole body expression of CD46, relationship between its expression and tumor growth and metastasis formation. Moreover, as a recently discovered target, molecular imaging of CD46 could contribute to understand specific molecular alterations related to CD46 expression. The goal of this proposal is the technical development of a platform for molecular imaging of CD46. We will develop a panel of radiopharmaceuticals capable of non-invasively imaging CD46. This platform will not only has the potential to identify mCRPC patients that will likely respond to CD46 ADC and other emerging therapies but also to explore CD46 expression in other tumor types with special attention to those that currently has very poor prognosis and survival. The information gather in this project may play an important role in the development on new therapies.