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. 2026 Jan 26;60(3):204–220. doi: 10.1007/s13139-025-00979-1

Current Status of PSMA-Targeted Agents Based on Small Molecules for Prostate Cancer in Preclinical Studies

Ayman Muzammal 1,2, Kyo Chul Lee 1,2, Sairan Eom 1,✉
PMCID: PMC13247089  PMID: 42273657

Abstract

Prostate-specific membrane antigen (PSMA) has emerged as a clinically validated target for the diagnosis and treatment of prostate cancer using radioligand therapy (RLT). Among various PSMA-targeting ligands, urea-based small-molecules have gained limelight due to their favorable pharmacokinetic properties, high tumor penetration and convenient radiolabeling. Current preclinical research focuses on enhancing in vivo efficacy by optimizing ligand design, radionuclide selection, and improved pharmacokinetics. To reduce off-target toxicity in organs and enhance tumor accumulation, strategies involving the incorporation of albumin-binding moieties or linker modifications have been explored. Various studies have focused on PSMA-targeted therapies labeled with radionuclides, including β emitters (lutetium-177), α emitters (actinium-225 or astatine-211), and Auger electron emitters (iodine-125), that provide unique DNA damage mechanisms tailored to the tumor size and disease stage. This review summarizes recent approaches of PSMA-targeted small-molecules to optimize therapeutic efficacy while minimizing adverse effects on healthy tissues for RLT of prostate cancer.

Keywords: Prostate cancer, Prostate‐specific membrane antigen, PSMA-targeting small-molecules, Preclinical radioligand therapy

Introduction

Prostate cancer is the second most commonly diagnosed cancer in men worldwide, accounting for approximately 15% of all male cancer incidences and is responsible for a significant proportion of new cancer cases and cancer-related deaths in the male population [1, 2]. Early-stage prostate cancer can often be managed with local treatment modalities such as cancer radical prostatectomy or radiotherapy but clinical management becomes much more difficult in advanced stages, especially metastatic or castration-resistant prostate cancer (CRPC) [3]. Although therapeutic approaches including surgery, hormone therapy, and chemotherapy have been developed and applied to treat prostate cancer, however ongoing treatment for patients with advanced or metastatic prostate cancer are still limited and recurrences are frequent [4]. This suboptimal efficacy is primarily due to tumor heterogeneity, the emergence of resistance to androgen deprivation therapy and inadequate responses to systemic treatments [5, 6]. These limitations have led to increasing interest in developing targeted molecular therapies that can specifically select and bind to tumor-associated biomarkers to improve therapeutic efficacy and reduce systemic toxicity and damage to healthy tissues.

One such targeted approach is radioligand therapy (RLT), that combines tumor-specific ligands with therapeutic radionuclides to selectively deliver cytotoxic radiation to cancer cells while sparing normal tissues. By integrating the precision of molecular targeting with the therapeutic efficacy of radionuclide therapy, RLT has demonstrated promising outcomes in tumor control and reduction of systemic toxicity compared with conventional treatments [7]. In prostate cancer, RLT primarily targets prostate-specific membrane antigen (PSMA), a type-II transmembrane glycoprotein that has emerged as one of the most promising molecular targets for theranostic purpose. PSMA is extremely overexpressed on the surface of prostate cancer cells, particularly in high-stage and high-grade tumors, hormone resistance, metastatic diseases, and CRPC, where its expression is associated with tumor aggressiveness [8, 9]. Although recent literature has reported the salivary glands as dose-limiting organs in PSMA-targeted RLT, it is well known that PSMA is also physiologically expressed at low levels in normal tissues [10]. This restricted expression pattern between malignant and normal tissues provides the potential for highly specific therapeutic delivery while minimizing off-target toxicity such as salivary gland damage for the development of PSMA-targeted agents. Therefore, PSMA is currently regarded as one of the most promising targets for imaging and therapy in the field of nuclear medicine for prostate cancer [11].

Among various PSMA-targeted agents, small-molecule ligands have attracted considerable interest in both imaging and therapeutic applications due to their advantages over antibodies and nanoparticles, including low molecular weight, rapid blood clearance, deeper tumor penetration, and convenient radiolabeling [12, 13]. Most PSMA-targeted small molecules are based on a glutamate-urea-lysine (glu-urea-lys) scaffold, which mimics the natural substrate of PSMA and provides high affinity and specificity [14]. By conjugating these ligands with therapeutic radionuclides, such as β-emitters (lutetium-177), α-emitters (actinium-225, astatine-211), or Auger emitters, selective irradiation of PSMA-positive tumor tissues can be achieved while sparing surrounding normal cells [15, 16]. Although clinical trials have shown promising results, particularly with agents such as [177Lu]Lu-PSMA-617 [17], continued preclinical studies remain crucial. Preclinical studies not only facilitate the discovery and optimization of new ligand and radionuclide combinations, but also enable detailed pharmacokinetic analysis, toxicity profiling, and the exploration of combination therapies. In this review, we focus on recent advances and key roles of PSMA-targeted small-molecules in preclinical development to provide guidance for therapeutic application of prostate cancer from the viewpoint of nuclear medicine.

Small-Molecule PSMA Ligands

In nuclear medicine, PSMA structure for targeting involves a PSMA binding domain, which is the part of the agent that recognizes and binds to the PSMA protein on cancer cells, and a domain to attach a therapeutic or imaging radionuclide [18]. This structure consists of a binding moiety (like small molecules or antibodies), a linker connecting the binder, and a radionuclide (Fig. 1) [19]. Anti-PSMA monoclonal antibodies, small molecule inhibitors, and PSMA-specific aptamers have been used as binding moieties for PSMA targeting [20]. PSMA-targeting antibodies offer high specificity to prostate cancer cells enabling accurate imaging and targeted therapy, but they also have drawbacks, including long circulation times that delay optimal imaging, the potential for nonspecific side effects and immunogenic response [21]. PSMA-specific aptamers, short DNA/RNA oligonucleotides, have attracted attention due to their high specificity and binding affinity with faster tissue penetration and tumor internalization and non-immunogenic nature as compared to antibodies. However, they are prone to nuclease degradation and structural modifications that can compromise binding affinity, and their small size also leads to much rapid renal clearance, thereby limiting circulation time and sufficient tumor accumulation [22]. On the other hand, small molecules have emerged most prominently, due to their high tumor penetration, faster blood clearance that minimizes non-specific binding and enhances tumor-to-background contrast, as well as the ease of radiolabeling, making them highly suitable for both imaging and therapeutic applications [23]. Small molecules for PSMA targeting have been extensively studied not only for their favorable pharmacokinetics but also for their diverse chemical structures, which influence binding affinity and radiolabeling strategies. In particular, PSMA-I&T and PSMA-617, labeled with lutetium-177 ([177Lu]Lu-PSMA-I&T and [177Lu]Lu-PSMA-617), are both representative small molecule PSMA-targeting radioligands used in targeted therapy of prostate cancer [24]. In addition, various radiolabeled small molecules (Fig. 2) like [68Ga]Ga-PSMA-11, [18F]DCFBC, [18F]DCFPyL, [123I]MIP-1072 and [123I]MIP-1095 have shown considerable efficacy and widespread use for molecular imaging [25–28].

Fig. 1.

Fig. 1

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Molecular structure of PSMA highlighting its distinct structural domains and key ligand binding sites. It includes a short intracellular domain, a central transmembrane region, and a large extracellular portion. The extracellular region has two domains of unknown function connected by proline-rich and glycine-rich linkers, an important catalytic domain containing the substrate-binding site targeted by PSMA inhibitors such as antibodies or small molecules and a terminal domain of unknown function containing a helical dimerization motif. Adapted from Puik JR et al., Crit Rev Oncol Hematol. 2025;205:104556. Copyright © 2025 by the authors. Licensed under CC BY 4.0 [19]

Fig. 2.

Fig. 2

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Chemical structure of important PSMA-ligands

PSMA-targeting small molecule inhibitors are chemically classified into three main groups: phosphorus-based, thiol-based, and urea-based compounds (Fig. 3) [29]. Before urea-based ligands emerged as main strategy for targeting PSMA due to their superior binding affinity, significant efforts were made for the development of phosphorus-based PSMA inhibitors such as 2-PMPA, GPI 5232 and GPI 18431 as well as thiol-based PSMA ligands such as 2-MPPA and E2072. Phosphorus-based PSMA inhibitors face two main challenges; in vivo competition with endogenous phosphates and a reversible internalization profile. However, thiol-based PSMA ligands are susceptible to oxidation, which can compromise their metabolic stability and trigger undesirable immune responses [30]. Among these three, urea-based small molecules, consist of a glu-urea-lys binding motif, a linker, and a radiolabeling moiety, demonstrate the highest binding affinity for PSMA and serve as the primary scaffold in the development of novel ligands [14]. The glu-urea-lys pharmacophore has been covalently functionalized with different chelators, such as DOTA (1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetraacetic acid), DOTAGA (1,4,7,10-tetraazacyclododecane,1-(glutaric acid)−4,7,10-triacetic acid), NOTA (1,4,7-triaza-cyclononane-1,4,7-triacetic acid) and HBED-CC (N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid) for radiometals labeling. These macrocyclic bifunctional chelators are particularly advantageous because they enable efficient and stable radiolabeling with radiometals (gallium-68 and lutetium-177) [31].

Fig. 3.

Fig. 3

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Representative chemical structures of PSMA-targeting small molecule inhibitors. Phosphorus-based compound (1) 2-PMPA, and compound (4), thiol-based compound (2) and (3), and urea-based compounds (5) and (6). Adapted from Gourni E, et al., Molecules. 2017;22:523. Copyright © 2017 by the authors. Licensed under CC BY 4.0 [29]

Beyond the choice of chelator, other structural components, particularly the linker and the radiolabeling moiety also play a pivotal role in determining the pharmacokinetic and pharmacodynamic behavior of PSMA-targeting small molecules [32]. A rational linker design can significantly improve tumor specificity and pharmacokinetics by reducing non-specific organ uptake and enhancing tumor-to-background contrast [33]. The choice of radionuclide also influences the therapeutic outcome of PSMA-targeted agents by determining the type and range of radiations emitted, which affects tumor cell killing efficacy, tissue penetration, and off-target toxicity [34]. Structural modifications in these components directly impact safety profiles by reducing radioligand accumulation in susceptible organs like kidneys and salivary glands, which are common dose-limiting sites during PSMA-targeted therapy [10]. These structure-functional relationships have led to the rational development of novel radiolabeled PSMA-targeted ligands, which are now being investigated for their optimized therapeutic performance, safety and radiolabeling versatility.

Preclinical Studies of PSMA-targeted Agents

For RLT of prostate cancer, PSMA-targeted small molecules are currently be labeled with various therapeutic radionuclides, including beta (β), alpha (α), and Auger electron emitters, each offering distinct properties that influence their therapeutic efficacy, tissue penetration, and off-target toxicity profiles as summarized in Table 1 [35, 36]. Based on their distinct physical and biological characteristics, the choice of radionuclide in PSMA-targeted therapy depends on tumor size, location, and treatment goal. β-emitters possess a lower linear energy transfer (LET) (~ 0.2 keV/μm), leading predominantly to the induction of DNA single-strand breaks (SSBs) as the primary mechanism of cytotoxicity. Their relatively longer tissue penetration (0.05–12 mm) enables a crossfire effect, enhancing dose uniformity within the tumor mass and making them more suitable for treating medium to large tumors [37]. On the other hand, α-emitters are ideal for small-volume disease or micrometastases due to their high LET (80 keV/μm) and short path length (40–100 μm), which induce dense ionization leading to irreparable DNA double-strand breaks (DSBs), thereby enabling potent cytotoxicity with minimal impact on surrounding healthy tissue [38]. Although α-radiation is highly effective in damaging tumor cells, its clinical use is limited by off-target toxicity to normal tissues expressing PSMA, such as the salivary glands, thereby restricting the maximum safe dose [39]. Auger electron emitters, characterized by extremely short range (2–500 nm) and moderate-to-high LET (4–26 keV/µm), require precise intracellular localization to achieve therapeutic efficacy, making them particularly suitable for targeting single cells or microscopic lesions when delivered with highly specific carrier molecules [40, 41]. Due to the distinct therapeutic characteristics of radionuclides as compared in Table 1, extensive research has been conducted to identify optimal small molecules and radioisotopes capable of effectively targeting PSMA for the treatment of prostate cancer. In this session, recent advances of PSMA-targeted agents for RLT of prostate cancer in preclinical studies are investigated as shown in Table 2.

Table 1.

Comparison of physical and biological characteristics of α, β particles, and Auger electron

Radionuclide Energy Range LET1) DNA damage
Beta (β) 50–230 keV  ≤ 12 mm  ~ 0.2 keV/μm SSBs2)
Alpha (α) 4–9 MeV 40–100 μm 80 keV/μm DSBs3)
Auger electron 25–80 keV 2–500 nm 4–26 keV/μm DSBs
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1) LET: Linear Energy Transfer, 2) SSBs: Singal Strand Breaks, 3) DSBs: Double Strand Breaks

Table 2.

Comparison of Alpha, Beta, and Auger-labeled Urea based PSMA small-molecules

Type of radionuclide Radionuclide Small molecule Cell line In vitro assay Tumor uptake
(%ID/g) at 24 h		 T/K ratio at 24 h Ref
Beta-emitter Lutetium-177 HTK01169 LNCaP Competition Binding, Ki = 0.04 nM 55.9 0.45 [42]
Lutetium-177 HTK03121 LNCaP Competition Binding, Ki = 2.40 nM 104 3.06 [43]
Lutetium-177 HTK03123 LNCaP Competition Binding, Ki = 1.76 nM 70.8 3.66 [43]
Lutetium-177 PSMA-ALB 02 PC3-PIP Uptake = 60% and Internalization = 26% cell binding at 4 h 76.4 7.16 [44]
Lutetium-177 PSMA-ALB-05 PC3-PIP Uptake = 60% and Internalization = 20% cell binding at 4 h 79.4 3.38 [44]
Lutetium-177 PSMA-ALB-07 PC3-PIP Uptake = 63% and Internalization = 22% cell binding at 4 h 84.6 1.64 [44]
Lutetium-177 PSMA-ALB-53 PC3-PIP Uptake = 59% and Internalization = 25% cell binding at4 h 53.8 2.17 [45]
Lutetium-177 PSMA-ALB-56 PC3-PIP Uptake = 55% and Internalization = 17% cell binding at 4 h 103.9 10.8 [45]
Lutetium-177 RPS-061 LNCaP IC50 = 4.1 nM 18.7 0.45 [46]
Lutetium-177 RPS-063 LNCaP IC50 = 1.5 nM 21.0 0.40 [46]
Lutetium-177 RPS-066 LNCaP IC50 = 5.2 nM 11.9 1.92 [46]
Lutetium-177 RPS-067 LNCaP IC50 = 9.5 nM 5.7 1.25 [46]
Lutetium-177 RPS-068 LNCaP IC50 = 2.1 nM 26.8 0.30 [46]
Lutetium-177 RPS-069 LNCaP IC50 = 3.8 nM 12.9 0.95 [46]
Lutetium-177 RPS-071 LNCaP IC50 = 10.8 nM  ~ 7.5 3.2 [47]
Lutetium-177 RPS-072 LNCaP IC50 = 6.7 nM 34.9 4.7 [47]
Lutetium-177 RPS-077 LNCaP IC50 = 1.7 nM 27.4  ~ 0.9 [47]
Iodine-131 RPS-027 LNCaP IC50 = 15 nM 8.13  ~ 3 [48]
Copper-64 DOTHA2-PSMA LNCaP IC50 = 64 nM, Uptake = 34.5 and Internalization = 34.1% IA/106 cells over 48 h 23.8 (%ID/cc) N/A [49]
Alpha-emitter Lead-212 CA012 C4-2 Competition Binding, Ki = 24.3 nM and Internalization = 15.6%IA/106 cells 7.81 4.85 [50]
Lead-212 NG001 C4-2 Binding affinity, Kd = 22.0 ± 4.1 nM and internalization = 21.0%IA/106 cells 13.6 1.41 [51, 52]
Actinium-225 L1 PC3-PIP Uptake, Clonogenic survival (N/A) 49.0 32.6 [53]
Bismuth-213 L1 PC3-PIP Uptake, Clonogenic survival (N/A) N/A N/A [53]
Astatine-211 3-Lu PC3-PIP Uptake = 13.4% IA and Internalization = 27.7% cell bound 9.46 130 [54]
Astatine-211 PSMA-1 LNCaP Uptake = ~ 22% uptake/mg protein at 30 min 8.7 N/A [55]
Astatine-211 PSMA-5 LNCaP Uptake = ~ 43% uptake/mg protein at 30 min 40.7 N/A [55]
Astatine-211 PSMA-6 LNCaP Uptake (data N/A) 18.1 N/A [55]
Astatine-211 NpG-PSMA PC3-PIP Uptake = ~ 54% uptake/mg at 4 h 41.08 62.2 [56]
Auger-emitter Iodine-125 DCIBzL PC3-PIP Competition binding Ki = 0.01 nM, Subcellular localization = 14% in perinuclear area N/A N/A [57]
Cobalt-58 m DOTA-PSMA-617 PC3-PIP Subcellular localization of PC3-PIP = 9.7% IA/106 and LNcaP = 12.6% IA/106 at 4 h in nucleus 6.2 7.0 [58]
Cerium-134 PSMA-617 PC3-PIP Uptake = 89.6% and Internalization = 34.8% cell binding at 4 h 4.5 7.3 [59]
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Ki = Inhibition constant, Kd = Dissociation Constant, IC₅₀ = Half maximal inhibitory concentration, IA= Incubated Activity, ID/g = Injected Dose per gram, T/K = Tumor-to-Kidney ratio, ~ indicate the approximate value

Beta Emitter Labeled PSMA-Targeted Agents

For prostate cancer RLT, β-emitters such as lutetium-177, iodine-131, yttrium-90, copper-67 and terbium-161 have been investigated by labeling with PSMA-targeted small molecules [60]. Among the various β-emitters labeled PSMA-targeted agents, [177Lu]Lu-PSMA-617 (Fluvicto) has emerged as a representative treatment for mCRPC, receiving FDA approval in 2022 [61, 62]. This approval was based on multiple clinical studies demonstrating its favorable safety profile and significant therapeutic efficacy, including high rates of prostate specific antigen (PSA) decline and manageable adverse events. Notably, [177Lu]Lu-PSMA-617 showed superiority over conventional therapies in delaying disease progression, as confirmed in major clinical trials like the TheraP and VISION studies, which compared this treatment to other standard options [63–68].

Although, [177Lu]Lu-PSMA-617 shows favorable therapeutic efficacy, its associated toxicities such as xerostomia and hematologic adverse events have prompted ongoing preclinical efforts to optimize its structure for enhanced tumor targeting and reduced off-target effects [68]. A major limitation of current PSMA-targeting radioligands is their relatively rapid blood clearance, which can compromise tumor uptake and reduce therapeutic efficacy. To address this, the researchers have focused on structural modifications particularly the incorporation of albumin-binding moiety (ABM) to prolong their circulation time and enhance tumor accumulation [69]. For example, [177Lu]Lu-HTK01169, a close derivative of PSMA-617 incorporating a highly lipophilic ABM (N-[4-(p-iodophenyl)butanoyl]-Glu) had enabled strong reversible binding to serum albumin, thereby reducing the fraction of unbound radioligand in plasma (< 1% vs ~ 17% for PSMA-617). It also showed enhanced PSMA affinity (Ki = 0.04 ± 0.01 nM), representing a six-fold improvement over [177Lu]Lu-PSMA-617 (Ki = 0.24 ± 0.06 nM). This translated to enhanced peak tumor uptake (55.9 ± 12.5%ID/g) in LNCaP xenografts, a 3.7-fold increase relative to [177Lu]Lu-PSMA-617 (15.1 ± 5.58%ID/g). Dosimetry analysis revealed an 8.3-fold higher tumor absorbed dose, enabling a 4-fold reduction in administered activity to achieve an equivalent median survival (4.6 MBq vs. 18.5 MBq). However, the improved tumor dose was accompanied by a substantial increase in normal organ exposure, most notably a 17.1-fold higher kidney radiation dose [42]. Following HTK01169, subsequent analogues HTK03121 and HTK03123 (Fig. 4) were developed by combining the tranexamic acid-9-anthrylalanine (affinity-modifying group) with N-(4-(p-chlorophenyl)butanoyl)-Gly and N-(4-(p-methoxyphenyl)butanoyl)-Gly (as ABM) respectively. By replacing the Glu in the N-(4-(p-iodophenyl)butanoyl)-Glu group with Gly removed the free carboxylate responsible for excessive kidney uptake, while substituting the highly lipophilic iodo group (LogP = 3.39) with less lipophilic chloro and methoxy groups (LogP = 2.59 and 2.08 respectively) accelerated renal clearance, together improving tumor-to-kidney dose ratios. This dual optimization also enhanced tumor uptake; 86% increase for [177Lu]Lu-HTK03121 and 23% for [177Lu]Lu-HTK03123 compared to [177Lu]Lu-HTK01169, with [177Lu]Lu-HTK03121 achieving peak tumor uptake values as high as 104%ID/g. The kidney uptake was significantly reduced, yielding approximately 62% lower renal absorbed dose relative to [177Lu]Lu-HTK01169. As a result, these analogues achieved 6.0- and 4.1-fold increase in tumor-to-kidney absorbed dose ratios compared to [177Lu]Lu-HTK01169, and significantly outperformed [177Lu]Lu-PSMA-617 with 2.9- and 2.0-fold higher ratios, respectively. Enhanced blood retention was modest, consistent with albumin binding, but no significant marrow dose concerns were observed [43].

Fig. 4.

Fig. 4

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Structural optimization of HTK01169 leading to HTK03121 and HTK03123 to enhance tumor-to-kidney absorbed dose ratio. This research was originally published in JNM. Kuo HT, et al. 177Lu-Labeled Albumin-Binder-Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio. J Nucl Med. 2021;62:521–7. © SNMMI [43]

In parallel, other urea-based ligands, PSMA-ALB-02, PSMA-ALB-05, and PSMA-ALB-07 incorporating 4-(p-iodophenyl) butyric acid as the ABM have been developed to enhance tumor targeting and pharmacokinetics. These ligands differ in linker composition, with [177Lu]Lu-PSMA-ALB-05 and [177Lu]Lu-PSMA-ALB-07 containing additional D-aspartate residues aimed at modulating hydrophilicity and renal clearance. Tumor uptake at 24 h post-injection was highest for [177Lu]Lu-PSMA-ALB-07 (84.6 ± 14.2%ID/g) followed by [177Lu]Lu-PSMA-ALB-05 (79.4 ± 11.1%ID/g) and [177Lu]Lu-PSMA-ALB-02 (76.4 ± 2.5%ID/g). However, kidney retention varied substantially: [177Lu]Lu-PSMA-ALB-02 showed the lowest renal uptake (10.7 ± 0.92%ID/g), whereas [177Lu]Lu-PSMA-ALB-05 and [177Lu]Lu-PSMA-ALB-07 showed elevated kidney accumulation (23.9 ± 4.02 and 51.9 ± 6.34%ID/g respectively), raising concerns about potential nephrotoxicity [44]. Further optimization of ABM and linkers resulted in two novel compounds, both combine a PSMA-binding motif and a DOTA chelator with distinct ABM: a 4-(p-iodophenyl)butyric acid in PSMA-ALB-53 and a p-(tolyl)butyric acid in PSMA-ALB-56 (Fig. 5). Tumor uptake in PSMA-positive PC-3 PIP xenografts was similar for both [177Lu]Lu-PSMA-ALB-53 and [177Lu]Lu-PSMA-ALB-56. However, [177Lu]Lu-PSMA-ALB-53 showed 15-fold higher plasma protein binding and prolonged blood retention due to the strong albumin-binding affinity of the 4-(p-iodophenyl) moiety compared to the p-(tolyl) moiety in [177Lu]Lu-PSMA-ALB-56, resulting in a 5-fold lower tumor-to-blood ratio and potentially higher off-target exposure. In contrast, [177Lu]Lu-PSMA-ALB-56 cleared faster through the kidneys due to reduced serum albumin binding, yielding a 3-fold higher tumor-to-kidney ratio and reduced nephrotoxicity risk. Compared to [177Lu]Lu-PSMA-ALB-02, [177Lu]Lu-PSMA-ALB-56 increased tumor uptake by 25% and lowered kidney retention by 30%. In therapeutic evaluations, [177Lu]Lu-PSMA-ALB-56 also outperformed [177Lu]Lu-PSMA-617 at equal doses, significantly delaying tumor growth and extending survival, with no observed toxicity [45].

Fig. 5.

Fig. 5

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Chemical structure of (a) PSMA-ALB-53 and (b) PSMA-ALB-56

Another innovative approach focused on designing dual-target binding ligands capable of simultaneously binding PSMA and human serum albumin (HSA) for modulating pharmacokinetics. A series of novel urea-based ligands (RPS-001, RPS-005, RPS-020, RPS-022, RPS-023, RPS-025, RPS-026, and RPS-027 (Fig. 6) with varying affinities for PSMA and HSA, were labeled with iodine-131. Among all, [131I]RPS-027 showed balanced kinetics (IC₅₀ = 1–10 nM and Kd = 11 μM), with highest tumor uptake (12.41%ID/g) at 3 h, kidney uptake of 15.21%ID/g at 12 h reducing to 1.0%ID/g at 48 h and tumor-to-kidney ratios > 2 by 18 h. It also exhibited strong and prolonged tumor uptake, efficient clearance from blood within 48 h, and lower kidney accumulation compared to MIP-1095 [48]. Limitations in radionuclide choice and binding optimization of RPS-027 laid the foundation of a new class of trifunctional ligands (RPS-061, RPS-063, RPS-066, RPS-067, RPS-068 and RPS-069), combining PSMA-binding moiety (triazolylphenylurea), an ABM (Nε-(2-(4-iodophenyl)acetyl)lysine) and a bifunctional chelator (p-SCN-Bn-DOTA) linked via polyethylene glycol (PEG) chains of varying lengths (PEG4, PEG3, PEG8, PEG12, PEG0, and PEG6, respectively) compatible with various radiometals (gallium-68, lutetium-177, actinium-225). PSMA affinity remained high (IC₅₀ = 1–10 nM) across all ligands exhibiting an inverse correlation with linker length. Among all ligands, [177Lu]Lu-RPS-063 (IC₅₀ = 1.5 ± 0.3 nM) showed the highest tumor uptake (30.0 ± 6.9%ID/g) exceeding that of [177Lu]Lu-PSMA-617, although kidney uptake remained a concern [46]. Following this, RPS-071, RPS-072 and RPS-077 (Fig. 7) were developed, all featuring the common structural scaffold of RPS-063 comprising PSMA-targeting moiety linked to DOTA via a PEG3 spacer. RPS-063 and RPS-071 contained Nε-(2-(4-iodophenyl)acetyl)lysine, while RPS-072 and RPS-077 incorporate 4-(4-iodophenyl)butanoic acid as the ABM. In RPS-063 and RPS-077, the ABM was directly coupled to the core through a peptide bond, while in RPS-071 and RPS-072, the ABM was separated by an additional PEG8 linker. These structural variations had minimal impact on PSMA affinity but significantly influenced albumin binding and pharmacokinetics. In LNCaP xenograft models, [177Lu]Lu-RPS-072 (IC₅₀ = 6.7 ± 3.7 nM) showed highest tumor uptake (34.9 ± 2.4%ID/g) at 24 h and a 1.5-fold greater tumor AUC than [177Lu]Lu-RPS-063, along with a superior tumor-to-kidney AUC ratio (4.7 ± 0.3 vs 0.4 ± 0.02 respectively) due to stronger ABM. The extended PEG linker (in RPS-071 and RPS-072) modestly enhanced blood clearance and markedly accelerated kidney clearance without impacting tumor retention. Overall, fine-tuning of the ABG and PEG linker length effectively optimized albumin binding, resulting in improved tumor retention and better therapeutic efficacy with reduced off-target toxicity [47].

Fig. 6.

Fig. 6

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Chemical structure of RPS series compounds and their affinities for PSMA and HAS. This research was originally published in JNM. Kelly JM, et al. Dual-Target Binding Ligands with Modulated Pharmacokinetics for Endoradiotherapy of Prostate Cancer. J Nucl Med. 2017;58:1442–9. © SNMMI. [48]

Fig. 7.

Fig. 7

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Chemical structure of four structurally related trifunctional PSMA-targeting small molecules. This research was originally published in JNM. Kelly JM, et al. Albumin-Binding PSMA Ligands: Implications for Expanding the Therapeutic Window. J Nucl Med. 2019;60:656–63. © SNMMI [47]

Meanwhile, therapeutic PSMA radioligands often lack suitability for PET imaging, which is critical for patient selection and treatment monitoring, so they are typically paired with diagnostic PSMA agents; commonly exemplified by the [68 Ga]Ga/[177Lu]Lu-PSMA-617 theranostic pair. However, discrepancies between imaging-based PSMA expression and therapeutic response have been observed in some cases, resulting in suboptimal clinical outcomes. To overcome these limitations, [64Cu]Cu-DOTHA2-PSMA was evaluated preclinically as a novel theranostic agent for prostate cancer because copper-64 allows for simultaneous or sequential use for both imaging (using the β+ emissions for PET scans) and therapy (using the β− and Auger electrons). The compound demonstrated strong PSMA-targeting characteristics, including high binding affinity (IC50 = 64 ± 50 nM) and internalization (34.1 ± 4.9%IA/106 at 48 h) in LNCaP cells. In vivo PET analysis showed higher tumor uptake (23.8 ± 11.5%IA/cc at 4 h) in [64Cu]Cu-DOTHA2-PSMA group, which was significantly reduced in blocking group (p < 0.05). Biodistribution studies revealed low kidney accumulation (< 15.8 ± 7.0%ID/g), while liver uptake was relatively higher (30.2 ± 4.2%ID/g at 4 h). Therapeutically, [64Cu]Cu-DOTHA2-PSMA extended survival in treated mice more effectively than the [natCu]Cu-DOTHA2-PSMA control group (p < 0.001) and slightly better than [177Lu]Lu-PSMA-617 (p = 0.09) with manageable toxicity and minimal off-target effect (Fig. 8). This approach offers a complementary theranostic option with a unique mechanism involving both β-particles and high-LET Auger electrons, enabling more personalized treatment [49]. While conventional β-emitters like lutetium-177 are clinically established; their relatively low LET and longer tissue penetration can limit efficacy, particularly in micrometastatic or heterogeneous tumor environments as much of the emitted energy is dissipated over millimeter distances instead of being deposited within targeted tumor cells. This limitation dictates the growing interest in alternative approaches such as α-particle radiotherapy to improve therapeutic outcomes.

Fig. 8.

Fig. 8

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Chemical structure of theranostic agent [64Cu]Cu-DOTHA2-PSMA (a). PETC/CT image of LNCaP tumor-bearing NRG mice at 4 h post injection (b). Probability of survival (%) in comparison to non-radiactive control and [177Lu]Lu-PSMA-617 (c). This research was originally published in JNM. Milot M-C, et al. The journey to a novel theranostic for prostate cancer: the preclinical study of.64Cu-DOTHA2-PSMA. J Nucl Med. 2022;63:4025. © SNMMI [49]

Alpha Emitter Labeled PSMA-Targeted Agents

PSMA-targeting ligands labeled with α-emitting radionuclides such as actinium-225, astatine-211, lead-212, radium-223 and thorium-227 have gained increasing attention in preclinical due to their high LET and potent cytotoxic effects against tumor cells [70]. Among these, [225Ac]Ac-PSMA-617 has been the most extensively studied, showing remarkable efficacy in patients with mCRPC, including those resistant to prior β-therapy [71]. However, limitations such as off-target salivary gland toxicity and limited global availability have shifted the focus towards alternative α-emitters. 212Pb-labelled compounds such as [212Pb]Pb-CA012 [50] and [212Pb]Pb-NG001 [51, 52] have emerged as promising candidates with potent tumor control and favorable safety profiles in preclinical models. The ongoing research indicates that these agents are now moving from preclinical development into clinical investigation. Parallel efforts were made to develop 223Ra-tagged PSMA-targeted agents using macropa-chelator, but it faced significant challenges, including in vivo instability and poor tumor delivery [60]. Comparative studies with high LET α-therapy, [225Ac]Ac-L1 and [213Bi]Bi-L1, confirmed its superior efficacy over β-therapy, [177Lu]Lu-L1, in both xenograft and micrometastatic prostate cancer models. In the micrometastatic model, single-dose [177Lu]Lu-L1 (37 MBq) showed no survival benefit (47 vs 48 days in control), whereas single dose [225Ac]Ac-L1 (37 and 74 kBq) significantly prolonged median survival (56 and 79 days). Fractionated [225Ac]Ac-L1 (9.3 kBq × 6) achieved the greatest median survival (72 vs 44 days in controls) and effectively delayed tumor growth without inducing off-target toxicity [53].

Astatine-211 is emerging as a promising radionuclide gaining attention due to its short half-life (7.2 h) and reliable cyclotron-based production. A novel 211At-labelled PSMA-targeting radiotracer ([211At]At-3-Lu) was designed with the goal of an optimized pharmacokinetic profile to enhance therapeutic efficacy. In PC3-PIP xenograft models, [211At]At-3-Lu showed dose-dependent tumor growth suppression with favorable biodistribution characteristics. Unlike earlier 211At-labelled compounds such as DCABzL, HS-549, GV-620 and GV-904, [211At]At-3-Lu demonstrated comparatively little deastatination and exhibited minimal uptake in non-target organs such as salivary glands and kidneys confirmed by stable blood parameters, normal tissue chemistries, and histology over long-term observation [54]. To further refine targeting specificity and therapeutic index, additional 211At-labelled PSMA ligands such as PSMA-1, PSMA-5, and PSMA-6 were synthesized using the [18F]F-PSMA-1007 scaffold (Fig. 9). An aryl boronic acid was introduced for 211At-labeling of PSMA precursors, replacing the N,N,N-trimethyl-2-pyridinaminium group used for 18F labeling. The three PSMA analogs differ in side-chain residues: Gly-Lys (PSMA-1), (R)-Glu-(R)-Glu (PSMA-5), and (S)-Glu-(S)-Glu (PSMA-6). Tumor retention of [211At]PSMA-5 was markedly higher than that of [211At]PSMA-1 and [211At]PSMA-6 (30.6 ± 17.8, 12.4 ± 4.8, and 19.1 ± 4.5%ID/g) at 3 h and (40.7 ± 2.6, 8.7 ± 3.5, and 18.1 ± 2.2%ID/g) 24 h respectively, with minimal deastatination (≤ 1% free astatide in urine at 3 h). [211At]PSMA-5 exhibited strongest tumor growth suppression, reducing tumor volume by 72% at 4 weeks post-treatment, compared with [211At]PSMA-1, which reduced tumor volume by 45%. [211At]PSMA-5 also showed minimal off-target toxicity, including xerostomia and nephrotoxicity, supporting its potential for clinical translation [55]. More recently, neopentyl-glycol-PSMA (NpG-PSMA), another [18F]F-PSMA-1007 analogue, was developed with a NPG moiety that stabilizes 211At-labeling and enhances its resistance to deastatination. [211At]At-NpG-PSMA (Fig. 10) was evaluated for its tumor-targeting performance, pharmacokinetics, safety profile, and in vivo stability. In comparison with agents like [211At]At-3-Lu which showed tumor uptake of 30, 17, and 10%ID/g at 1, 4, and 24 h, [211At]At-NpG-PSMA achieved high and sustained tumor accumulation of 48, 42, and 41%ID/g at 1, 3, and 24 h. Negligible accumulation in thyroid, salivary glands, and stomach at 3 h (0.28, 0.88, and 0.71%ID/g respectively), reflecting low deastatination of [211At]At-NpG-PSMA, compared with [211At]PSMA-5 (11, 11, and 5%ID/g respectively). Renal toxicity, a common dose-limiting factor in α-therapy, was observed to be minimal and reversible at therapeutically relevant doses, and no significant hematologic toxicity was reported [56].

Fig. 9.

Fig. 9

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Chemical structures of [211At]PSMA-1, [211At]PSMA-5, and [211At]PSMA-6 derived from the [18F]F-PSMA-1007. Adapted from Watabe, T, et al. Targeted α-therapy using astatine (211At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound. Eur J Nucl Med Mol Imaging. 2023;50:849–58. Copyright © 2023 by the authors [55]

Fig. 10.

Fig. 10

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Chemical structures of [211At]At-NpG-PSMA. Adapted from Yaginuma K, et al. Novel astatine (211At)-labelled prostate-specific membrane antigen ligand with a neopentyl-glycol structure: evaluation of stability, efficacy, and safety using a prostate cancer xenograft model. Eur J Nucl Med Mol Imaging. 2025;52:469–81. Copyright © 2025 by the authors [56]

The focus of RLT research is gradually shifting toward cocktail therapies that combine α and β-emitters. A recent study evaluated the therapeutic potential of [225Ac]Ac-PSMA-617 and investigated the in vivo effects of its combination with the [177Lu]Lu-PSMA-617 in preclinical models of prostate cancer. A four-arm study in xenografted nude mice assessed the therapeutic effects of monotherapy and combination regimens. In control group, tumor detectability remained 100%, but survival decreased from 56% at 3rd week to 0% in 4th week. Monotherapy groups, [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 maintained 100% survival until 3rd week, then decreased to 33% and 50% by 8th week, with tumor detectability declining to 78% and 60%, respectively. Mice receiving the combined [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 treatment (Fig. 11) showed the most favorable outcomes, including delayed tumor growth, 90% survival at 8th week and complete tumor regression in 40% of cases, as monitored by PET/CT and caliper measurements [72].

Fig. 11.

Fig. 11

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Representative [18F]AlF-PSMA-11 PET image of each treatment group 7 days (a) and 30 days (b) after treatment. Adapted from Savio E, et al., Nucl Med Biol. 2025;146–147:109,032. © 2025, with permission from Elsevier. Licensed under CC BY-NC-ND 4.0 [72]

Researchers are also exploring other cocktail therapies to combine PSMA targeted RLT with immunotherapy aims to amplify antitumor efficacy by exploiting various synergistic mechanisms. First, local cytotoxicity and subsequent immunogenic cell death is induced by PSMA-targeted agents (e.g., therapeutic radionuclides) that releases tumor antigens and damage-associated molecular patterns (DAMPs). This process effectively transforms immunologically "cold" tumors into "hot" phenotypes through enhanced dendritic cell maturation and antigen presentation and making them sensitize to immune checkpoint inhibitors. Second, PSMA ligands can be used to deliver immune-stimulatory agents, such as 4-1BB agonists or cytokines, ensuring their presence directly within the tumor microenvironment to enhance local immune activation. Third, radionuclide-induced DNA damage leads to antigen release that, when paired with anti-PD-1 therapy, generates tumor-specific memory T-cells to reduce tumor recurrence [73]. A similar investigation was done by using the combination of RLT ([225Ac]Ac-PSMA-617) and immune checkpoint blockade using an anti-PD-1 antibody in C57BL/6-mice bearing syngeneic RM1-PGLS tumors. The combination of [225Ac]Ac-PSMA-617 and an anti-PD-1 antibody significantly extended median survival to 51.5 days, compared to 37 days for anti-PD-1 alone and 32 days for RLT alone (Fig. 12). This result was statistically superior to either monotherapy (P ≤ 0.0251), providing strong preclinical evidence of combining these modalities to achieve synergistic therapeutic outcomes [74]. The promising preclinical results from this combination therapy strategy suggest a potential advancement in overcoming resistance in prostate cancer treatment. Furthermore, the development of theranostic agents compatible with novel radionuclides like lead-212, and astatine-211 supports the emergence of more personalized and scalable therapeutic paradigms.

Fig. 12.

Fig. 12

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Comparison of the survival (%) of C57BL/6 mice bearing RM1-PGLS tumors in different treatment groups. This research was originally published in JNM. Czernin J, et al. Immune-Checkpoint Blockade Enhances.225Ac-PSMA617 Efficacy in a Mouse Model of Prostate Cancer. J Nucl Med. 2021;62:228–31. © SNMMI [74]

Auger Emitter Labeled PSMA-Targeted Agents

Auger emitter-labeled PSMA-targeted agents have been developed to address the need for highly localized, potent therapies against micrometastatic prostate cancer. Unlike β and α-emitters, which have longer tissue penetration and can cause off-target toxicity, Auger electrons emit extremely short-range, high-LET radiation ideal for precise delivery to intracellular and preferably nuclear targets to maximize cytotoxicity. Successful efforts have designed small-molecule PSMA ligands such as [125I]DCIBzL (2-[3-[1-carboxy-5-(4-[125I]iodobenzoylamino)-pentyl]-ureido]-pentanedioic acid) (Fig. 13) with enhanced cellular internalization and nuclear proximity, optimizing the spatial localization of decay events. Kiess et al. developed a highly specific small-molecule PSMA-targeting agent, [125I]DCIBzL, to deliver iodine-125 selectively to prostate cancer cells. In vitro, treatment with [125I]DCIBzL induced significant DNA damage and reduced clonogenic survival in PSMA-positive PC3 PIP cells, but not in PSMA-negative PC3 flu cells. Confocal microscopy confirmed the compound localized to the perinuclear region and plasma membrane. In vivo, nude mice bearing PSMA-positive PC3 PIP xenografts treated intravenously with 111 MBq, [125I]DCIBzL showed strong tumor growth suppression, with only 1 of 6 mice reaching 5 × the initial tumor volume by day 60, compared with < 15 days in PSMA-negative tumors and all control groups (p = 0.002). The sustained tumor responses were likely due to the highest PSMA-binding affinity (Ki = 0.01 nM) of [125I]DCIBzL, ensuring prolonged tumor retention, and the long half-life (59 days) of iodine-125, providing continuous radiation exposure and effective DNA damage. No weight loss or acute renal and hematologic toxicity was observed at the administered dose. These findings demonstrated the therapeutic potential of PSMA-targeted Auger radiotherapy for selective eradication of prostate cancer micrometastases [57].

Fig. 13.

Fig. 13

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Chemical structure of [125I]DCIBzL. This research was originally published in JNM. Kiess AP, et al. Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen. J Nucl Med. 2015;56:1401–7. © SNMMI [57]

Based on this investigation, Shen et al. advanced the research by evaluating therapeutic potential of [125I]DCIBzL and its long-term safety in a micrometastatic prostate cancer model, more closely reflecting the clinical context of early metastatic disease using PSMA-positive PC3-ML cells in NSG mice. Treatment with ≥ 18.5 MBq of [125I]DCIBzL significantly delayed metastatic progression and prolonged survival from 6 weeks in controls to 11 weeks in the treatment group with no appreciable long-term toxicity observed over 12 months. Compared to α-emitters like [211At]At-PSMA-6, which exhibited dose-limiting nephrotoxicity with a maximum tolerated dose (MTD) of 37 kBq in CD1 mice, the MTD of [125I]DCIBzL exceeded 111 MBq. Dosimetry modeling confirmed selective tumor targeting and low renal exposure, supporting the potential of Auger-based PSMA-RLT as a safe and effective strategy [39]. Expanding upon prior efforts with iodine-based Auger emitters and in line with growing interest in PSMA-targeted Auger radiolands, Baun et al. investigated [58mCo]Co-DOTA-PSMA-617, for evaluating its therapeutic efficacy and safety in preclinical models. In vitro studies confirmed PSMA-specific uptake, significant nuclear accumulation, and dose-dependent reductions in cell viability and clonogenic survival (p < 0.05). In-vivo, the compound exhibited strong tumor targeting; two intravenous doses of 144 ± 9 MBq of [58mCo]Co-DOTA-PSMA-617 (at 7 and 14 day) significantly prolonged median survival compared to controls (23 days vs. 11 days, p = 0.0014). No weight loss, hematologic or organ toxicity was observed and salivary glands and bone marrow remained unaffected, supporting the potential of cobalt-based Auger therapy as an effective and safe approach for prostate cancer [58].

Recent investigations by Bobba et al. explored an Auger-based theranostic agent, [134Ce]Ce/[134La]La-PSMA-617, for both PET imaging and Auger electron therapy in prostate cancer models. The agent exhibited high radiochemical purity, excellent serum stability, and strong PSMA-specific binding and internalization in vitro. In vivo PET imaging and biodistribution studies demonstrated selective tumor uptake and rapid clearance from non-target tissues. A single-dose administration of [134Ce]Ce-PSMA-617 significantly prolonged survival in PSMA-positive tumor-bearing mice in a dose-dependent manner, with median survival extended from 33 to 80 days. These results suggest the promise of [134Ce]Ce-PSMA-617 as a dual-function agent, combining diagnostic imaging with effective Auger-mediated radiotherapy for micrometastatic prostate cancer [59]. Despite encouraging preclinical outcomes, PSMA-targeted small-molecules labeled with Auger emitters have not yet progressed to clinical approval and remain in early stages of development.

Conclusion

The emergence of small-molecule PSMA-targeted radioligands has transformed the management of advanced prostate cancer, paving the way for new therapeutic approaches. These low molecular weight urea-based compounds bind PSMA with high affinity, allowing rapid tumor penetration, faster systemic clearance, and efficient delivery of radionuclides. The clinical success of PSMA small molecule labeled with β-emitter, [177Lu]Lu-PSMA-617, has demonstrated significant survival benefits by delivering moderate-energy β-particles enabling effective treatment of both primary tumors and metastatic lesions. However, challenges such as acquired resistance and off-target toxicities, including xerostomia and myelosuppression, highlight the need for continued innovation.

To overcome these obstacles, preclinical research has explored advanced strategies to enhance therapeutic efficacy and safety. Rational PSMA ligand optimization through ABM and linker modifications have been attempted and the optimized one labeled with β-emitters improved pharmacokinetics, increasing tumor-to-organ dose ratios and prolonging anti-tumor effects in prostate cancer models. However, these efforts still come at the cost of increased renal retention, achieving the optimal balance between high tumor accumulation and minimal off-target exposure remains a central challenge in PSMA-targeted radioligand design. Moreover, the use of β-emitters, characterized by relatively low LET and long tissue penetration range, may limit their therapeutic efficacy in micrometastatic disease or within heterogeneous tumor microenvironments. PSMA ligands labeled with high-energy α-emitters have been developed, offering potent cytotoxic effects against micrometastatic prostate cancer. In addition, Auger electron emitters have emerged as promising candidates, providing highly localized cytotoxicity while minimizing collateral damage to surrounding healthy tissues.

PSMA-targeted RLT is moving toward personalized and combination approaches. The design of innovative combination therapies, which may involve pairing different classes of radionuclides or integrating radioligand therapy with other treatment modalities like immunotherapy, is a highly promising frontier. Continued progress in the development of novel theranostic agents and the establishment of sustainable, scalable isotope production methods are essential to unlock the full potential of PSMA-targeted therapies for broader clinical application.

Acknowledgements

We would like to thank Ms. Hwisoo Lim for supporting the drawing of compound structure.

Authors’ Contributions

Muzammal Ayman participated in data acquisition and analysis and drafting of the manuscript. Kyo Chul Lee participated in the study conception, and approval of the final content of the manuscript. Sairan Eom participated in the study design, drafting of the manuscript, and approval of the final content of the manuscript. All authors read and approved of the final manuscript.

Funding

This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), Ministry of Science and ICT (MSIT), Republic of Korea (No.50461–2025), and partly supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science and ICT) (No. RS-2021-NR056276 and RS-2022-NR072455).

Data Availability

Not applicable.

Declarations

Competing interests

Muzammal Ayman, Kyo Chul Lee, and Sairan Eom declare that they have no conflict of interest.

Human Ethics and Consent to Participate declarations

Not applicable.

Clinical Trial Number

Not applicable.

Consent for Publication

Not applicable.

Declaration of Generative AI in Scientific Writing

During the preparation of this work, the authors used ChatGPT (OpenAI) to check grammar and enhance readability of some sentences. After using this tool, the authors carefully reviewed and edited the content as necessary and take full responsibility for the final content of the publication.

Footnotes

This manuscript has not been published before or is not under consideration for publication anywhere else and has been approved by all co-authors.

Publisher's Note

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Change history

10/9/2026

This article was originally published under the subscription model but it is now published under an Open Access license.

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