A short review on the current status of PSMA ligands used for PSMA-PET/CT imaging

More than a decade ago, the introduction of PSMA-targeted prostate-specific membrane antigen (PSMA) ligands has revolutionized the imaging and treatment of prostate cancer (PCa) (Fig.  1). PCa is known as the most common cancer in men in western countries, making it the second leading cause of cancer-associated mortality in men [1]. Both in the setting of biochemical recurrence, as well as in primary and advanced stages of PCa, PSMA-targeted positron emission tomography/computed tomography (PET/CT) imaging has become increasingly popular for detecting even small metastases due to its superior sensitivity and specificity compared to conventional imaging techniques [2]. The introduction of ⁶⁸Ga- and ¹⁸F‑labeled PSMA ligands has significantly improved diagnostic performance for disease staging and management in patients with PCa. This short review focuses on the recent advances in the use of different PSMA radiotracers for PET imaging and depicts possible challenges, pitfalls, and emerging clinical applications.

Prostate-specific membrane antigen (PSMA), known as glutamate carboxypeptidase II, is a type II transmembrane protein consisting of 750 amino acids [3]. PSMA is significantly overexpressed in malignant prostate tissue, and is only weakly expressed in normal prostate tissue. Previous studies proved a strong correlation between PSMA expression and a higher Gleason score [4]. Moreover, PSMA is also overexpressed in the neovasculature and the newly formed vessels in a variety of solid tumors (e.g., renal cancer, breast cancer, colon cancer), as well as in the astrocytes of the central nervous system [5]. PSMA has gained interest as an important target for PET imaging. In the recent years, various small-molecule radiopharmaceuticals (PSMA inhibitors) have been developed, with a high affinity to the active substrate recognition site of the extracellular part of PSMA [5]. The protein possesses enzymatic activity and is considered to have a role in the folate uptake (FOLH1 gene); however, its function still remains unclear.

Due to the excellent diagnostic performance of PSMA-targeted PET/CT compared to other methods of imaging PCa, PSMA-targeted PET imaging has been shown to significantly improve the detection of metastatic sites, even at low serum PSA levels. At present, the indications for PSMA-ligand PET/CT include the initial staging of PCa in patients with risk features such as elevated serum PSMA values > 20 ng/ml or a higher International Society of Urological Pathology grade group (grade 3 or higher) [6]. Furthermore, in the setting of biochemical recurrent disease (BCR), which is defined as an increase in serum PSA values ≥ 0.2 ng/mL after primary curative treatment, even small recurrent PCa lesions (e.g., pelvic lymph nodes or local recurrence) can be visualized with PSMA-ligand PET/CT. Also, in advanced PCa patients, PSMA-ligand PET/CT plays a significant role for assessing eligibility for a ¹⁷⁷Lu-PSMA radioligand therapy.

To the best of our knowledge, at present, ⁶⁸Ga-PSMA-HBED-CC (known as ⁶⁸Ga-PSMA-11) is the most common used tracer in PSMA-targeted PET imaging worldwide [7]. Nevertheless, throughout recent years, ¹⁸F‑labeled PSMA-targeted PET ligands have gained increasing interest and would offer advantages with regard to their production amount, image resolution, and physical characteristics ([8]; Table 1). In 2008, ¹⁸F‑DCFBC was first introduced at the Johns Hopkins University [9] as the first generation of a PSMA-targeted ligand in PET imaging. In 2011, the second-generation radiotracer ¹⁸F‑DCFPyL was introduced: compared to the first-generation radiotracer, ¹⁸F‑DCFPyL showed five times higher affinity for PSMA, resulting in higher tumor-to-background ratios as well as improved biodistribution characteristics with a higher renal excretion rate [10]. More recently, another ¹⁸F‑labeled PSMA ligand, ¹⁸F‑PSMA-1007, has been introduced, demonstrating promising results with a primary hepatobiliary clearance. The nonurinary excretion of ¹⁸F‑PSMA-1007 might be advantageous for the detection of local recurrence in the prostate bed or pelvic lymph node metastases [11]. In 2023, ¹⁸F‑flotufolastat (¹⁸F‑rhPSMA‑7.3) was introduced and approved by the US Food and Drug Administration (FDA) for use in prostate cancer staging. A recent study by Rauscher et. al. demonstrated that a patient cohort that underwent ⁶⁸Ga-PSMA-11-PET were significantly more impacted by bladder activity compared to the cohort that underwent ¹⁸F‑flotufolastat-PET [12]. Another PSMA-tracer in clinical use with regulatory approval is ^99mTc-PSMA-I&S, which can potentially be used in an outpatient setting for SPECT imaging and was initially developed for radioguided surgery [13, 14]. ^99mTc-PSMA-RGS has been proved to be of great value in patients with recurrent PCa to successfully identify and remove metastatic lesions [13‐15].

Compared to the short-lived isotopes ¹⁸F and ⁶⁸Ga, another PSMA-targeted radiopharmaceutical with a significantly longer half-life of 12.7 h, ⁶⁴Cu-targeted PSMA, with an improved diagnostic and therapeutic potential, should be named. Due to its longer half-life and attractive physical characteristics for imaging, PET scans can be performed in facilities that are distant from cyclotron production, and thus scheduling may become easier [16]. Also, ⁶⁴Cu also emits positrons of lower energy, comparable to ¹⁸F isotopes, and thus provides a higher image resolution compared to ⁶⁸Ga isotopes [17]. ⁶⁴Cu is itself a theranostic agent, and forms a theranostic pair with 67 Cu, a β and γ emitter, enabling both imaging and radiotherapy for PCa [18]. Moreover, the shorter half-life of ⁶⁷Cu (T_1/2 = 2.58 days) compared to 177 Lu (T_1/2 = 6.7 days) shortens radiotherapy, while still remaining effective [19].

PSMA-targeted PET imaging has significantly improved the management of PCa patients. However, PSMA-positive findings and abnormalities in PCa staging can only be interpreted correctly if one is aware of the normal biodistribution pattern, and the various benign and malignant nonprostatic conditions with significant PSMA-radiotracer uptake, as these can easily be misinterpreted as false-positive imaging findings associated with PCa. In this short review, we mainly focus on the interpretative pitfalls which can be found in PSMA-targeted imaging with ⁶⁸Ga- and ¹⁸F‑labeled radioligands, as these PSMA-targeted PET tracers represent the two most common subgroups of PSMA-targeted radiopharmaceuticals. One of the most important pitfalls in PSMA-targeted PET imaging has been proven to be of benign origin, such as sympathetic chain ganglia [7], that are often misinterpreted as nonregional lymph node metastases. Other frequently observed pitfalls in PSMA-targeted PET imaging include PSMA-positive bone lesions, which can be misinterpreted as osseous metastases, as bone is the most common site in distant metastatic lesions in PCa patients. Accordingly, many benign bone lesions such as fibrous dysplasia, healing bone fractures, degenerative bone changes or Paget’s bone disease may show significantly increased radiotracer uptake due to reparative and remodeling processes and can mimic PCa bone metastases, especially in imaging with ¹⁸F‑labeled radiopharmaceuticals [20]. Increased PSMA-uptake has also been reported in noninfectious granulomatous diseases as sarcoidosis, which can mimic distant lymph node metastases. Many studies focused on the effect of prior androgen deprivation therapy (ADT) on PSMA expression and lesion detection, suggesting that the inhibition of the androgen receptor may result in an increase of PSMA expression in metastatic lesions [21].

In recent years, a variety of malignant nonprostate conditions, particularly solid tumors, have shown significant PSMA-radiotracer uptake due to PSMA expression in the tumor neovasculature, such as renal cell carcinoma [22], breast cancer [23], or lung cancer [24].

In this short review, the use of various new prostate-specific membrane antigen (PSMA)-targeted tracers in prostate cancer (PCa) molecular imaging has been discussed. PSMA-targeted molecular imaging has significantly improved the imaging and hence the management of PCa patients due to its specificity and membrane localization on tumor cells. However, one must be aware of the physiological distribution pattern, biokinetics, and possible interpretative pitfalls that are associated with the different radiotracers, which can mainly be subgrouped into ⁶⁸Ga- and ¹⁸F‑labeled radioligands. In recent years, new potential applications for PSMA-targeted imaging and therapies have emerged, as PSMA expression has been observed in various non-prostatic solid tumors, often associated with the tumor neovasculature. For this purpose, larger clinical trials are needed to further evaluate the application and limitation of this molecular imaging modality.

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