Description

Prostate cancer is the second most common cancer in men and the fifth leading cause of male cancer-related death. Incidence rates are higher in developed countries (37.5 per 100,000) compared to developing countries (11.3 per 100,000), with similar patterns in mortality rates. Currently, approximately 10 million men are diagnosed with prostate cancer worldwide, with over 400,000 deaths annually. By 2040, annual mortality is projected to reach over 800,000. Detection methods for prostate cancer include digital rectal examination, serum prostate-specific antigen (PSA), ultrasound, CT, MRI, and bone scans. While helpful, these methods have limitations, particularly in early detection, biochemical recurrence, and post-treatment assessment. Hence, there is a pressing need for sensitive and specific diagnostic agents capable of detecting and localizing tumors and small metastases for accurate diagnosis, staging, and recurrence assessment. In recent years, PET molecular imaging, which visualizes biochemical metabolism and specific target expression, has provided valuable insights into tumor biology. Prostate-specific membrane antigen (PSMA), a type II glutamate carboxypeptidase produced by prostate epithelial cells, is highly expressed in prostate cancer and its metastases, with minimal expression in other normal tissues (e.g., intestines, brain, kidneys) at levels significantly lower than in cancer tissues. This specificity makes PSMA a crucial target for prostate cancer imaging. Two PET radiotracers, 68Ga-PSMA-11 and 18F-DCFPyL, are now FDA-approved in the United States for imaging prostate cancer, particularly for detecting recurrence. While these tracers offer high sensitivity and specificity, there are still some limitations. On the one hand, despite the high sensitivity of PSMA PET/CT, false positives can occur due to benign prostate hyperplasia, prostatitis, or other non-cancerous conditions that may also express PSMA. Additionally, some low-grade or small tumors, as well as neuroendocrine-differentiated prostate cancers, may not express sufficient PSMA, resulting in false negatives. On the other hand, PSMA PET/CT primarily detects PSMA-expressing tissues but does not provide information on other tumor biological characteristics, which may limit its utility in therapeutic decision-making and prognostic assessment. Trophoblast cell surface antigen 2 (Trop2) is another promising target, highly expressed in various cancers. Antibody-drug conjugates (ADCs) targeting Trop2 have demonstrated clinical success in treating advanced triple-negative breast cancer, HR+/HER2- breast cancer, and urothelial carcinoma, offering new options for patients with late-stage cancers resistant to multiple treatments. Since ADC efficacy is closely linked to antigen expression, Trop2 levels serve as a critical marker for predicting Trop2-ADC effectiveness. Currently, Trop2 detection is limited to immunohistochemical staining of biopsy samples, which reflects only local expression and cannot represent Trop2 levels across entire tumors or metastases. Thus, a comprehensive, in vivo, dynamic method for Trop2 expression detection is needed. Our research team has successfully developed a Trop2-specific nanobody and constructed a novel Trop2 PET probe labeled with 68Ga. This probe effectively identifies Trop2 expression in different tumor models, showing favorable pharmacokinetics and tumor uptake. Initial clinical research suggests that 68Ga-MY6439 demonstrates higher uptake in prostate cancer than 18F-FDG and 68Ga-PSMA-11 PET/CT, detecting more lesions in certain cases with increased diagnostic sensitivity. Therefore, beyond patient selection for Trop2-ADC therapy, Trop2-targeted PET probes have potential as broad-spectrum imaging agents for malignancies, aiding in the diagnosis, staging, and therapeutic monitoring of aggressive cancers, potentially overcoming limitations seen with 18F-FDG and 68Ga-PSMA-11 PET/CT in certain tumor types.