Compounds incorporating astatine-211 (211At) show promise for targeted radiotherapy in treating prostate cancer; however, a significant challenge remains due to deastatination within the body. Researchers have now created a new molecule featuring a neopentyl glycol structure that effectively prevents this deastatination. This innovative structure could ensure that the harmful 211At is concentrated in tumors while sparing healthy tissues, thus enhancing treatment options for prostate cancer.
Prostate cancer ranks as the second most prevalent cancer in men globally, following lung cancer. In the U.S., nearly 300,000 new cases are diagnosed each year. Although reducing testosterone and other male hormones can effectively treat prostate cancer, this method loses efficacy once the disease progresses to metastatic castration-resistant prostate cancer (mCRPC). At this critical stage, the cancer progresses rapidly and becomes resistant to standard hormonal treatments and chemotherapy.
A promising approach to target mCRPC involves taking advantage of the fact that these tumor cells typically overproduce a membrane protein known as prostate-specific membrane antigen (PSMA). Specifically, targeted alpha therapy entails attaching a radioactive atom, such as actinium-225 (225Ac), to a compound that binds tightly to PSMA. As the radioactive atom decays, it releases alpha particles that are damaging to nearby cells, particularly tumor cells. However, due to the limited production of 225Ac, researchers are exploring other viable options.
In a recent study, a research team led by Professor Tomoya Uehara at Chiba University in Japan developed a new compound for targeted alpha therapy in prostate cancer using a different alpha-emitting radionuclide: astatine-211 (211At). The team included Hiroyuki Suzuki and Kento Kannaka from Chiba University, along with Kazuhiro Takahashi from Fukushima Medical University. Their research, published in Volume 9 of EJNMMI Radiopharmacy and Chemistry on June 17, 2024, addresses a key challenge of 211At-based compounds for this therapy: deastatination.
Deastatination refers to the process where enzymes in the body detach the 211At atom from the compound, effectively separating the therapeutic component from the PSMA-targeting element. This not only compromises the treatment’s effectiveness against cancer but also disperses a radioactive substance to healthy tissues, which can harm the liver, stomach, and kidneys.
To tackle this issue, the researchers referred to a chemical structure they had explored in the past. “We recently created a neopentyl derivative with two hydroxyl groups, termed an ‘NpG structure,’ which serves as a stable 211At-labeling moiety that can retain 211At within the body,” Uehara explains. “Based on our previous findings, we believed the NpG structure could be utilized to design numerous 211At-labeled derivatives targeting PSMA.”
The team tested their hypothesis by designing and synthesizing two derivatives, each featuring a different glutamic acid linker between the NpG structure and the PSMA-targeting region, known as asymmetric urea. These compounds were labeled as NpG-L-PSMA and NpG-D-PSMA.
Initially, the researchers conducted tests using iodine-125 (125I) linked to these compounds instead of 211At due to the greater availability and ease of procurement of 125I. Experiments performed on mice bearing tumors from a human prostate cancer cell line revealed that both [125I]I-NpG-D-PSMA and [125I]I-NpG-L-PSMA exhibited minimal accumulation in the stomach and thyroid, indicating their significant in vivo stability against deiodination. Notably, [125I]I-NpG-D-PSMA showed a greater accumulation in tumor tissue compared to [125I]I-NpG-L-PSMA.
Consequently, the team proceeded with another series of experiments using [211At]At-NpG-D-PSMA. Similar to its iodine-based counterpart, this compound showed significant accumulation in tumors and low levels in crucial organs like the liver and stomach.
The combined results from these in vivo experiments underscore the potential of NpG-D-PSMA in targeted alpha therapy. “Our study demonstrated that the neopentyl glycol structure, which can securely hold radiohalogens like 211At and 125I in vivo, may serve as a tumor-targeting agent. Utilizing the neopentyl glycol structure as a labeling moiety for radiohalogens could facilitate the development of radiopharmaceuticals for various tumor types, significantly benefitting human health,” Uehara concludes.
