A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer
Abstract
:1. Introduction
2. PSMA Expression
3. [99mTc]Tc-Labeling Approaches
3.1. [99mTc]Tc-Labeled Anti-PSMA Antibody and Derivatives
3.2. [99mTc]Tc-Housed PSMA-i
Chelator/Linker/Scaffold | Affinity | Performance | Ref. | |
---|---|---|---|---|
[Tc(CO)3]15–16 (2020) | | a 5.50 ± 0.99 (15) 0.20 ± 0.01 (16) | Complexes were investigated on 22Rv1 xenografts. Moderate PSMA-dependent tumor uptake 1.87 ± 0.11% ID/g, at 1 h p.i, which increased to 2.83 ± 0.26% ID/g at 4 h. Clinical translation: No | [118] |
| b 8.79 (17) | Complexes were investigated on LNCaP xenografts. PSMA mediated tumor uptake: 4.86 ± 1.19% ID/g at 1 h p.i. High kidneys 70.95 ± 12.28% ID/g and spleen 5.84 ± 1.51% ID/g uptakes. Tumor-to-blood ratio was 2.89 and tumor–to–muscle ratio was 12.46. Liver and intestinal uptake were 2.46 ± 0.72 and 2.16 ± 0.34% ID/g, respectively. Clinical translation: No | [119] |
Chelator/Linker | Scaffold | Affinity | Performance | Ref. | |
---|---|---|---|---|---|
[TcO]1–6 (2009) | | | a 176 (1) 60 (2) 13.8 (3) 31 (4) 102 (5) 338 (6) | Complexes were evaluated on LNCaP xenografts. High and stable PSMA-dependent tumor uptake (11.2% ID/g at 4 h p.i.). High kidney uptake 28.9% ID/g. Low non-target organs uptake (<1% ID/g at 4 h p.i.) High target-to-non target ratios Clinical translation: No | [116] |
[TcO]7–14 (2013) | | | b 0.03 (7) 0.13 (8) 1.91 (9) 7.99 (10) 0.18 (11) 0.05 (12) 0.17 (13) 2.73 (14) | Complexes were evaluated on PC3-PIP/PC3-flu xenografts. [TcO]7,11,14 are the best of the series. High and stable PSMA-dependent tumor uptake (26.81 ± 1.9–33.59 ± 3.20% ID/g at 2 h p.i.). High kidney uptake followed by slow washout. High spleen uptake followed by slow elimination Low non-target organ uptake (<2% ID/g at 1 h p.i.) High target-to-non target ratios Clinical translation: No | [106] |
[TcO]15,16 (2017) | | | c 47.6 ± 2.5 (15) 39.7 ± 1.2 (16) | [TcO]16 was evaluated on LNCaP xenografts. High PSMA-dependent tumor uptake (8.28 ± 3.27% ID/g at 1 h p.i.). High kidney uptake and spleen uptake. Low non-target organs uptake (<3% ID/g at 1 h p.i.). Clinical translation: Yes, Phase 2 | [115] |
HYNIC-PSMA-i Scaffold | Affinity | Performance Clinical Translation | Ref. | |
---|---|---|---|---|
[Tc-HYNIC]1 (2013) | | a 1.74 | Complexes were evaluated on PC3-PIP/PC3-flu xenografts. Whole-body SPECT-CT imaging show low PSMA-dependent tumor uptake and high background activity. Clinical translation: No | [106] |
[Tc-HYNIC]2 (2017) | | n.d | Complex was evaluated on LNCaP/PC3 xenografts. High and stable PSMA-dependent tumor uptake (9.84 ± 2.63%I D/g at 3 h p.i.). High kidney uptake followed by slow washout (12.63 ± 0.56%ID/g at 3 h p.i.). Low nontarget organs uptake (<2% ID/g at 1 h p.i.). High target-to-nontarget ratios: Tumor-to-blood 271 and tumor-to-muscle 246 at 3 h p.i. Clinical translation: Yes, phase 1 | [117] |
[Tc-HYNIC]3 (2017) | | n.d | Complex was evaluated on LNCaP/PC3 xenografts. High and stable PSMA-dependent tumor uptake (19.45 ± 2.14% ID/g at 2 h p.i). High kidney uptake followed by slow washout. Low nontarget organs uptake (<3% ID/g at 1 h p.i.) High target-to-non-target ratios: Tumor-to-blood 24.33 at 23 h p.i. Clinical translation: Yes, phase 1 | [109] |
[Tc-HYNIC]4-6 (2020) | | b 13.58 23.63 42.36 | Complexes were evaluated on LNCaP/PC3 xenografts. PSMA-dependent tumor uptake (3.62 ± 0.78–1.8 ± 0.32% ID/g at 2 h p.i.). High kidney uptake. Low nontarget organs uptake. Clinical translation: No | [110] |
[Tc-HYNIC]7 (2020) | | c 80 (7) | Complex was evaluated in healthy BALB/C mice. No data on LNCaP/PC3 xenografts were reported. Reduced kidney uptake (37.5 ± 9.5) at 4 h p.i. with respect to other 99mTc-PSMA. Low nontarget organs uptake (<1%ID/g at 4 h p.i). Clinical translation: Yes, phase 1 | [111] |
3.3. [99mTc]Tc-Labeled Nanoparticle Carrying PSMA-i
4. Clinical Investigations
5. Multimodal and Multipurpose Systems as the Ultimate Perspective in [99mTc]Tc-Housed PSMA-i
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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99mTc (SPECT) | 68Ga (PET) | 111In (SPECT) |
---|---|---|
PROS. Optimal nuclear properties (t1/2 = 6.02 h; Eγ = 140 keV). t1/2 is sufficiently long, allowing completing RP synthesis in radiopharmacies, distribution to hospitals, dose preparation, administration, and collection of clinically useful images. The monochromatic 140 keV photons (90% abundance) are ideal for obtaining SPECT imaging with high spatial resolution using commercial gamma cameras. Low radiation exposure to patients and to personnel due to the absence of corpuscular radiation. 99mTc half-life nicely matched the PK of small and medium-size peptides. On-site availability from inexpensive portable 99Mo/99mTc generator system, which overcomes the problem of worldwide distribution. Rich and versatile coordination chemistry. 99mTc-RPs are efficiently prepared in situ through commercially available lyophilized instant kits. 99mTc-RPs produce lower radiation effective doses than 68Ga-RP. Wider distribution of SPECT technology over PET. CONS. SPECT has lower spatial resolution (7–8 mm) than PET. The sophisticated Tc chemistry might complicate the setting of instant cold kits. | PROS. Good nuclear properties (t1/2 = 67.71 min; Eβ+ = 1899 keV). t1/2 is sufficiently long to allow the synthesis, purification, dose preparation of RP, administration and collection of clinically useful images. 68Ga t1/2nicely matched the PK of peptides On-site availability from portable 68Ge/68Ga-generator system. The long t1/2 of 68Ge (270.8 days) allows the utilization of a single generator for a long period (1/2 y). 68Ga RPs can be produced through the use of kits that consent to a wide availability of the corresponding imaging agents. PET higher image resolution (4–5 mm) and relevant features over SPECT. CONS. The low t1/2 does not allow for widespread shipping of the isotope. The amount of 68Ga obtainable from generator in a single elution is sufficient to synthetize the tracer for only one or two patients, limiting the number of investigations for a single day. The higher energy of 68Ga positron with respect to 18F, can lead to lower spatial resolution and high radiation dose to the patients. The are fewer PET cameras installed worldwide with respect to SPECT ones. This limits the utility of this modality in daily clinical practice. | PROS. The long t1/2 (2.8 d) makes this radionuclide useful for SPECT imaging of biomolecules with slow kinetics, such as antibodies and their fragments. CONS. Suboptimal nuclear properties (t1/2 = 2.8 d; Eγ = 171 and 245 keV with 91% and 94% abundance, respectively). The high energy both γ rays produce low spatial resolution using commercial gamma cameras. Restrict availability of 111InCl3 due to the cyclotron production. High production costs. |
Tc(V) Oxo/Dioxo Core | Tc(V)-HYNIC | Tc(I)-Tricarbonyl | [Tc(V)N(PNP)]2+ | |
---|---|---|---|---|
Coordinating System (denticity; donor atoms set) | Tetradentate; N2S2 N3S, N4 | EDDA/Tricine; N2O2 | Bi- or Tridentate; His-based ligands, polyamino-polycarboxylate, polyamines, aromatic and aliphatic amines, cyclopentadienyl ligands | Bidentate; Cys-based ligands [H2NS]−, [OS]2− |
Coupling BFC-molecular vector | Difficult, potentially stressful for the molecular vector. Tetradentate ligand utilizes a carboxylic acid side-group to link biomolecules. Such ligands can be conjugated via carboxylic acids (COOH), amino (NH2), and thiocyanate (NCS) groups to biomolecules. | Easy, bioconjugate chemistry. HYNIC- conjugates are produced via an amide linkage formed by the reaction of the active ester derivative of the ligand. | Easy bioconjugate chemistry. The His-based chelator can be readily incorporated into the peptide chain by using traditional automated synthesis (peptides) or His-tag (proteins). | Easy, bioconjugate chemistry. The Cys-chelator can be readily incorporated into any peptide using standard solid- or solution-phase coupling methodologies; for proteins, native Cys-residues can be used or additional small Cys-terminal peptides can be attached even site-specifically. |
Labeling | One-step | Two-step | One or Two-step | One or two-step |
Labeling Temperature | Heating (75–100 °C) | Heating (60–100 °C) or RT | Generally heating (75–100 °C). | Heating (80–100 °C) or RT |
Purification | No, very difficult if necessary | No, easy if needed | No, easy if needed | No, easy if needed |
Chemical identification | Yes | No, difficult | Yes | Yes |
Isomerism | Yes, two isomers (syn, anti) separable and individually evaluable. | Yes, several isomeric forms, not separable and not individually evaluable. | Potentially yes. | Yes, two isomers (syn, anti) separable and individually evaluable, having the same affinity for the target. |
Complex Stability | Generally stable | Stable | Very stable | Very stable |
Flexibility against chemical-physical modulation | Low, minimal variation of chelator backbone or by modification/insertion of PKM | Medium by chemical modification of Tricine and EDDA or by insertion or modification of a PKM | Medium by chemical variation of the chelator and modification/insertion of PKM | High by chemical modification of the substituent on PNP, variation of chelator and modification/insertion of PKM |
Kit formulation | One vial | One vial | One/two vials | Two vials |
Feasibility for 188Re | Yes | No | Yes | Yes |
Chelator Linker Scaffold | Affinity | Performance | Ref. | |
---|---|---|---|---|
[Tc(CO)3]1–7 (2008) | | a 10.75 (1) 0.50 (2) 10.34 (3) 0.17 (4) 0.91 (5) 199.56 (6) 2.06 (7) | Complexes were evaluated on PC3-PIP/PC3-flu xenografts. PSMA-dependent tumor uptake picked at 0.5–1 h p.i, followed by rapid washout. Rapid clearance from the kidneys. High spleen uptake followed by elimination. Clinical translation: No | [105] |
[Tc(CO)3]8–10 (2013) | | b 15.25 1.12 (8) 12.60 (9) 16.30 (10) | Complexes were evaluated on PC3-PIP/PC3-flu xenografts. [Tc(CO)3]8 is the best of the series. High and stable PSMA-dependent tumor uptake picked at 0.5 h p.i, uptake (28.31 ± 4.4% ID/g at 0.5 h vs. 23.22 ± 6.02% ID/g at 5 h p.i). High kidney uptake followed by slow washout. High spleen uptake followed by elimination. Clinical translation: No | [106] |
[Tc(CO)3]11–14 (2013) | | c 4.35 ± 0.35 (11) 1.75 ± 0.32 (12) 0.64 ± 0.46 (13) 1.07 ± 0.89 (14) | Complexes were investigated on LNCaP/PC3 xenografts. High and stable tumor uptake ranged from 9.3 to 12.4% ID/g at 1 h p.i and 7.2–11.0% ID/g at 4 h. High tumor-to-blood ratios ranging from 29:1 to 550:1 and tumor–to–muscle ratios ranging from 31:1 to 157:1 at 4 h. Liver and intestinal uptake were <1% ID/g for all compounds. Rapid clearance from the kidneys. Low spleen uptake. Clinical translation: Yes | [34,107,108] |
Agent | Formulation/Radiosynthesis | Indication | Pros/Cons |
99mTc-TrofolastatConcluded Phase 3 (ClinicalTrials.gov Identifier: NCT02615067) | Two-vial kit formulation, the composition and the procedure were not deeply described. Labeling: 1° step NaTcO4(40 mCi/1 mL saline) was added to the Isolink vial. Heat to 95 °C for 30 min. 2° Step: pH was adjusted to 7.5 with HCl.; PSMA-i (0.100 mg) was added. Heat to 95 °C for 30 min. Voltot= n.d RCY 85%. Purification: by HPLC RCP ≥ 98%. Specific activity: 37 TBq/mmol. | Useful to assist in the initial diagnosis of PCa, the monitoring of disease progression and the response to the therapeutic treatment by SPECT imaging. | Pros. Lower urinary excretion, which allows for detecting PCa in the pelvic area at early stages of the disease. Successfully detected very small PCa lesions (<10 mm) in bone, LNs, and prostate gland, thus suggesting that SPECT/CT scan with this agent may provide prognostic information for both primary tumor and biochemical recurrence. Detection rates (50%) slightly lower than that of 68Ga-PSMA-11 at low PSA levels (0.2–1 ng/mL). Cons. Detection rates (50%) slightly lower than that of 68Ga-PSMA-11 at low PSA levels (0.2–1 ng/mL). |
99mTc-PSMA-I&S Phase2 (ClinicalTrials.gov Identifier: NCT04832958) | One vial: SnCl2, tartrate, PB pH 8, PSMA-I&S (35–40 µg). Labeling: NaTcO4 (20–30 mCi/1–5 mL), was added to the vial. pH 7.5–8, heat to 90 °C for 20 min. RCY 99%. Diluted to 10 mL. Am44–52 GBq/µmol. | Useful to localize small metastases of PCa and to perform RGS with the main advantage of the immediate confirmation and removal of metastasis prior of the histological analysis. Superior substitute of 111In PSMA-I&T. | Pros. Good visualization of the lesion also those previously identified with 68Ga-PSMA11. High accumulations in LNs metastases, allowing for the exact intraoperative identification ad resection during RGS. Cons. Lesion-to-background contrast is achieved after 5 h p.i. Detection rates in patients with biochemical recurrence and low PSA levels (<4 ng/mL), are lower than that reported for 68Ga-PSMA and for 99mTc-Trofolastat. |
99mTc-EDDA/HYNIC-PSMA Phase 1 | Two-vial kit formulation. 1 lyophilized vial: SnCl2 (0.020 mg), EDDA (20 mg), tricine (40.8 mg) mannitol (0.102 mg), HYNIC-PSMA-i (0.102 mg). 2° vial: Phosphate Buffer, 0.2 M pH 7. Labelling: to vial 1 was added PB (1 mL) and NaTcO4 (20–30 mCi/1.0 mL). Heat to 95 °C for 10 min. RCY ≥ 98%. | Useful to assist in the initial diagnosis of PCa and the monitoring of disease progression. by SPECT imaging. Suitable in planning RGS or for identification of PSMA+ lesions before consideration of radioligand therapy, e.g., with 177Lu-PSMA. | Pros. Faster blood clearance and urinary excretion, which allow the visualization, at 3 h p.i., of PCa in the pelvic area at early stage of diseases. Lower liver uptake and lowest effective radiation dose than 99mTc-Trofolastat. Able to localize the lesions in bone, soft tissues and LN. Lesion detection rate of 78.3% with respect to Ga-68 PSMA. Cons. Lower sensitivity than 68Ga-PSMA-11 for small-sized lesions. Only 28% of LNs lesions < 10 mm were detected, hence its use is not recommended in patients with small-volume disease. |
99mTc-HYNIC-ALUG Phase 1 | HYNIC-ALUG (0.010 mg), EDDA (0.5 mL of 20 mg/mL in 0.1 M NaOH solution), Tricine (0.5 mL of 40 mg/mL in PBS 0.2 M, pH = 6.0). NaTcO4 (50 mCi/1.0 mL). SnCl2 (50 μL of 1 mg/mL in 0.1 M HCl solution). Heat to 100 °C for 15 min. Voltot = 2.050 mL RCY ≥ 98%. | Useful to assist in the initial diagnosis of PCa and the monitoring of disease progression by SPECT imaging. This is also proposed for RGS. | Pros. Efficient detection of the metastasis at PSA level greater than 1.30 ng/mL Cons. The high accumulation in the kidneys makes difficult the interpretation of scintigraphic images. |
99mTc-PSMA-T4Phase 1 | Sterile and apyrogenic freeze-dry kit: PSMA-T4 (20 mg), Tricine (50 mg), EDDA (5 mg), SnCl2 (40 mg), Na2HPO4x12H2O (29 mg),/NaH2PO4x2H2O (3.0 mg). Labelling: NaTcO4 (20–30 mCi/1.0–2.5 mL). Heat to 95 °C, 10 min. RCY ≥ 95%. | Useful to assist in the initial diagnosis of PCa and the monitoring of disease progression. Suitable for RGS and for identification/assessment of PSMA+ lesions before consideration of radioligand therapy. | Pros. RP is efficiently prepared in a short time by freeze-drying PSMA-T4 kit. Favorable distribution and kinetic behavior which allow the visualization of the PSMA + lesions within 3 h p.i. Cons. The high accumulation in the kidneys and renal excretion can cause difficulties in images interpretation. |
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Brunello, S.; Salvarese, N.; Carpanese, D.; Gobbi, C.; Melendez-Alafort, L.; Bolzati, C. A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer. Molecules 2022, 27, 2617. https://doi.org/10.3390/molecules27092617
Brunello S, Salvarese N, Carpanese D, Gobbi C, Melendez-Alafort L, Bolzati C. A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer. Molecules. 2022; 27(9):2617. https://doi.org/10.3390/molecules27092617
Chicago/Turabian StyleBrunello, Sara, Nicola Salvarese, Debora Carpanese, Carolina Gobbi, Laura Melendez-Alafort, and Cristina Bolzati. 2022. "A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer" Molecules 27, no. 9: 2617. https://doi.org/10.3390/molecules27092617