PSMA for PET Imaging of Prostate Cancer

Prostate cancer is the most commonly diagnosed cancer in men worldwide. Among men in the United State, prostate cancer is the third leading cause of death from malignancy.1 According to American Cancer Society, about 1 man in 7 will be diagnosed with prostate cancer during his lifetime.2 Prostate cancer develops mainly in older men. About 6 cases in 10 are diagnosed in men aged 65 or older, and it is rare before age 40. The average age at the time of diagnosis is about 66. Prostate cancer has high cure rate when detected early. Molecular Imaging technologies dramatically improve prostate cancer diagnosis and treatment. Although FDG is the most widely use PET tracer, using FDG for PET/CT imaging in prostate cancer is limited because a large fraction of prostate cancer shows limited FDG uptake.3 In the past decade, alternative tracers for prostate cancer imaging are radiolabeled choline derivative such as 18F-fluorocholine and 11C-choline. They are used as PET tracers for staging and restaging of prostate cancer.4 According to a meta-analyses report, in primary nodal imaging the specificity is as high as 95% but the sensitivity is very poor (49%).5 Due to the lack of sensitive imaging for prostate cancer, more research has been focused on the development of new tracers that have better sensitivity and specificity. In recent years, targeting the prostate specific membrane antigen (PSMA) with 68Ga-labeled and 18F-labeled PET tracers has gained highest clinical impact.

ISSN 2287-0237 (online)/ 2287-9674 (print) Several imaging probes specifically targeting PSMA were developed. Since the 1980s, several studies have been made to target specific regions of the intracellular or extracellular domain of PSMA with monoclonal antibodies labeled with different isotopes for nuclear medicine imaging. 11 One of the first PSMA imaging agents was 111 In-labeled anti-PSMA antibody ( 111 In-capromab pendetide, ProstaScint ® ). 12 The effectiveness of antibodies as diagnostic radiopharmaceuticals is limited by a long circulating half-life resulting in a high unspecific background activity and poor tumor penetrability. Thus, the application of 111 In-capromab pendetide for imaging of prostate cancer is limited because it has high non-specific uptake and relatively poor tumor-to-background ratios.
Besides the development of PSMA monoclonal antibodies, small molecule PSMA inhibitors with high affinity gained a lot of interest. Because of their small size, they have better tumor penetration than antibodies. A series of studies have been made to evaluate the role of small molecule inhibitors of PSMA labeled with 123 I, 99m Tc, 18 F, 111 In, and 68 Ga. [13][14][15][16][17][18][19][20][21][22][23][24] PSMA inhibitors fall into 3 families: urea-based, phosphorous-based, and thiol-based 25 as shown in Figure 1. A study by Chen et al., compared PSMA ligands with different linker lengths and has shown that an increased linker length enhanced the affinity for PSMA and increased tumor uptake. 26 Urea-based inhibitors have a high affinity and specificity for PSMA and fast and efficient internalization into the cells. Several clinical studies evaluating PSMA ligands have been performed. Examples of small molecule PSMA ligands are shown in Figure 2. Among these agents, the 68 Ga-and 18 F-labeled compounds have attracted the most attention because they can be used for PET/CT imaging. Currently, the most widely used PET tracer for prostate cancer imaging is 68 Ga-PSMA-11. 24 68 Ga-PSMA-11 has many synonyms. Here is the list of 68 Ga-PSMA-11 in difference writing.   Ga-PSMA-11 68 Ga-PSMA-11 has a disadvantage with respect to production capacity and nuclear properties. The half-life of 68 Ga is only 68 minutes. Therefore, delivery of sufficient amount of tracer activities to a remote center is quite challenging. 68 Ga (Gallium-68) is produced with 68 Ge (Germanium-68) generator. Preparation of 68 Ga-PSMA-11 is relatively easy. One batch of production of 68 Ga-PSMA-11 can be used with 2-4 patients per generator elution. The main advantage of 68 Ga-PSMA-11 is the commercially availability of 68 Ge/ 68 Ga generators. The long half-life of 68 Ge (271 days) permits the generator to be used for several months or up to a year. The short half-life of 68 Ga (68 minutes) allows multiple elution of the generator on the same day. For a center that does not have access to a cyclotron and has a moderate number of patients, the price of these generators is a reasonable investment. 68 Ge/ 68 Ga generator was first developed in 1950. The first commercial 68 Ge/ 68 Ga generator was introduced in late 1990s which resulted in the blossoming of the 68 Ga-PET. Pharmaceutical grade generators appeared on the market in 2014. Examples of commercial 68 Ge/ 68 Ga generator are shown in Figure 3. A generator is a self-shield system housing a parent/daughter radionuclide mixture in equilibrium. Figure 4 shows a schematic presentation of the cross section of a column-based generator. Commercial generators consist of a short chromatographic column packed with a solid support in a shielding container. 68 Ge which is produced from a high energy cyclotron from stable 69 Ge isotope is absorbed onto a column filled with inorganic, organic or mixed matrix. 68 Ge decays to 68 Ga and 68 Ga decays to stable 68 Zn as shown in Figure 5. 68 Ga is washed off the column with an appropriate solution. Then 68 Ga can be used for tracers labeling.   . The chelator HBED-CC allows labeling with kit formulations at room temperature without critical radiochemistry demands. 27 68 Ga-PSMA-11 can be prepared by several methods. It can be prepared with an automate synthesis system which can provide the reliability, reproducibility and safety of radiopharmaceutical productions. In recent times, the widespread, routine clinical use of 68 Ga-PSMA-11 demands availability of a ready-to-use kit formulation to enable convenient radiopharmaceutical preparation. A freeze-dried kit vial for formulation of 68 Ga-PSMA-11 was developed by a number of centers. 28,29 This method will provide convenient preparation of 68 Ga-PSMA-11. Satpati D., et al reported that 68 Ga-PSMA-11 could be prepared in >98 % radiochemical yield and purity using the freeze-dried kit vials. The development of a simple and ready-to-use freeze-dried kit for preparation of 68 Ga-PSMA-11will contribute to a major step towards the widespread use of 68 Ga-PSMA-11 for prostate cancer imaging with PET/CT. 68 Ga has physical half-life of only 68 minutes. Therefore, delivery of sufficient radiopharmaceutical activities to a remote center is challenging. One batch of 68 Ga-PSMA-11 production can be used with 2-4 patients. In large centers with many patients, several productions per day are required, or multiple generators are needed to produce sufficient amount of activities. The centers which have quantitative demand, the use of 18 F-labeled PSMA tracers may be more efficient. High activities of 18 Figure 6. Due to longer half-life of 18 F and the possibility to produce in high activity, the 18 F-labeled PSMA enable centralized production and delivery to distant centers. 18 F has a lower positron energy than 68 Ga (0.68 MeV for 18 F vs. 1.90 MeV for 68 Ga). Thus PET imaging with 18 F-labeled tracers have better spatial resolution than 68 Ga-labeled tracers.
Besides diagnostic imaging, radiolabeled PSMA ligands also have potential for radionuclide therapy of prostate cancer. Several PSMA ligands are currently investigated clinically for diagnostic and therapeutic purposes. Some PSMA ligands can be labeled with either 68 Ga for PET imaging or 177 Lu (Lutetium-177) for radionuclide therapy. 177 Lu physical properties are good to use as therapeutic radionuclide. 177 Lu is a medium-energy beta emitter (490 keV) with a maximum tissue penetration of < 2 mm. The emission characteristics match the lesion size/volume to be treated to ideally focus energy within the tumor rather than in the tissue surrounding the lesion. 177 Lu has a relatively long physical half-life of 6.73 days. These physical properties of 177 Lu allow for the delivery of a high radiation dose to prostate cancer cells. These PSMA ligands which can be labeled either with 68 Ga or 177 Lu have potential to be used for both diagnostic and therapeutic purposes. Example of such agents are PSMA I&T and DKFZ-617. PSMA I&T (for Imaging and Therapy) is DOTAGA-(I-y)fk(Sub-KuE). It is DOTAGA-couple PSMA ligands by increasing the hydrophilicity of the ligand by substitute DOTA by 1,4,7,10-tetraazacyclodocecane-, 1-(glutaric acid)-4,7,10-triacetic, resulting in DOTAGA-FFK(Sub-KuE) which can be labeled with both 68 Ga and 177 Lu.30 DOTA-conjugated DKFZ-617 PSMA ligand is another tracer which has mainly been used for therapy may be used for diagnostic application too. The results show that 177 Lu-PSMA is a safe treatment option for metastatic prostate cancer patients and has a low toxicity profile.
Positive responses to therapy in terms of decline in PSA are reported and more than 40% of patients showed more than 50 % PSA decline. 31,32 Comparison of the properties of 68 Ga, 18 F, and 177 Lu is shown in Table 1.

Conclusion
It appears that PSMA shows great promise not just in detecting prostate cancer, but also as a target for radionuclide therapy. At present, there are many radiolabeled PSMA ligands available for imaging and therapy. 68 Ga-PSMA-11 is currently the most widely used for prostate cancer imaging with PET/CT. Development of 18 F-PSMA shows promising results. In the future, PSMA imaging will be used more widely due to the availability of tracers. The use of PSMA PET/CT resulted in a change of the therapeutic management in up to 50% of cases. The currently available data clearly shows that PSMA imaging has a clinical impact on the diagnosis of prostate cancer. Radiolabeled PSMA tracers also have high potential for therapeutic approaches.

Acknowledgements
The author thanks the PET center and Cyclotron facility team at Wattanosoth Cancer Center including doctors, nurses, physicists, technologists, chemists, engineers and pharmacists. During the past 12 years, they have put a lot of effort into continued improvements in quality and range of services. Also, the author is very grateful for the support from the executive of the Bangkok Hospital and Wattanosoth Cancer Hospital. • Beta-decay: 490 keV • X-ray: 113 keV (3%), 210 keV (11%) • Medium-energy (beta)-emitter and maximal tissue penetration of <2 mm provide better irradiation of small tumors than longer (beta)-range.