Summary

Peptide Receptor Radionuclide Therapy (PRRT) utilizing radiolabeled somatostatin analogs, especially [¹⁷⁷Lu]Lu‑DOTA-TATE, has become a standard treatment for SSTR2-positive neuroendocrine neoplasms (NENs), including metastatic pheochromocytomas and paragangliomas (PCC/PGL). Despite its clinical success, challenges such as suboptimal blood retention, limited lutetium-177 supply, and imaging constraints highlight the need for alternative approaches. Copper radionuclides, such as [⁶⁷Cu]Cu‑SARTATE and [⁶⁴Cu]Cu‑SARTATE, offer promising theranostic applications by combining β-therapy with copper-67 and PET imaging with copper-64. Recent advancements include albumin-binding TATE variants with NODAGA chelators for copper labeling, which have shown enhanced tumor uptake in preclinical models. This study evaluates the theranostic efficacy of copper-labeled TATE variants ([⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE and [⁶⁷Cu]Cu‑NODAGA-TATE) in comparison with [¹⁷⁷Lu]Lu‑DOTA-TATE using a pheochromocytoma mouse model. The study focuses on radioligand binding, tumor uptake, pharmacokinetics, dosimetry, anti-tumor efficacy, and hematologic and renal safety. Quantitative SPECT imaging, conducted with Mediso NanoScan® SPECT/CT, allows for detailed biodistribution analysis, supporting the potential of copper-based radioligands for enhanced theranostics in SSTR2-positive tumors.

Figure 1. Clinically approved TATE variants for theranostic application in the management of SSTR2-positive neuroendocrine neoplasms and experimental variants (this work) for theranostic use of radiocopper; pharmacokinetic properties of the diagnostic variants [⁶⁴Cu]Cu‑NODAGA-TATE and [⁶⁴Cu]Cu‑NODAGA‑cLAB4-TATE in tumor-bearing mice have been reported previously 24; (cLAB4) 'clickable' lysine-derived albumin binder 4; (EMA) European Medicines Agency; (FDA) Food and Drug Administration of the United States; (GEP) gastroenteropancreatic; (NENs) neuroendocrine neoplasms.

Results with nanoScan® SPECT/CT

1. SPECT imaging of copper‑67-labeled NODAGA-TATE variants in tumor-bearing mice

The in vivo theranostic performance of [⁶⁷Cu]Cu‑NODAGA-TATE and [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE was compared to [¹⁷⁷Lu]Lu‑DOTA-TATE in subcutaneous MPC allograft mice. SPECT imaging quantified tissue distribution and kinetics over seven days following equal initial activity doses. All radioligands showed tumor and kidney uptake with renal excretion (Figure 3 A). Copper‑67-labeled NODAGA-TATE variants demonstrated superior count rates and spatial resolution in SPECT imaging compared to [¹⁷⁷Lu]Lu‑DOTA-TATE (details in Supporting Information, Figure S 5 A-F).

Figure 3. Distribution, tissue-specific pharmacokinetics and cumulated activity of lutetium‑177- and copper‑67-labeled TATE variants in MPC allograft mice measured by quantitative SPECT imaging; animals received 50 MBq of the radioligands each prepared at different molar activities corresponding to molar amounts of 1.25 nmol (Am = 40 MBq/nmol) and 2.5 nmol (Am = 20 MBq/nmol) at treatment start; (A) Maximum-intensity projections of SPECT images at indicated time points and scaling; image series from treatments with radioligands at a molar activity of 40 MBq/nmol; (B-C) Time-courses of tissue-specific activity concentration after treatment; (D) Tissue-specific mean cumulated volume activity calculated from areas under curves; (E) Time-courses of excreted activity; data presented without decay correction as means ± standard error; significance of differences: * p < 0.05 ** p < 0.01, *** p < 0.001.

2. Pharmacokinetics of copper‑67-labeled NODAGA-TATE variants in tumor-bearing mice

Quantitative SPECT analysis revealed activity concentration time courses and effective half-lives in blood, liver, kidneys, and tumors. While [⁶⁷Cu]Cu‑NODAGA-TATE and [¹⁷⁷Lu]Lu‑DOTA-TATE showed similar rapid blood clearance, [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE exhibited prolonged blood retention due to albumin binding. Tumor uptake of [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE was 60% higher with extended retention (effective half-life: 14.6 h), resulting in four-fold higher tumor cumulated activity than [⁶⁷Cu]Cu‑NODAGA-TATE and comparable levels to [¹⁷⁷Lu]Lu‑DOTA-TATE. Despite its improved tumor retention, [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE demonstrated a lower tumor-to-blood ratio and slightly higher tumor-to-kidney ratio compared to [⁶⁷Cu]Cu‑NODAGA-TATE. Further kinetic details are provided in the Supporting Information (Figures S6-S10, Table S3).

3. Projected human doses for treatment with copper‑67-labeled NODAGA-TATE variants

Quantitative SPECT data from female MPC allograft mice enabled the estimation of projected human pharmacokinetics and radiation doses for [⁶⁷Cu]Cu‑NODAGA-TATE, [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE, and [¹⁷⁷Lu]Lu‑DOTA-TATE. Extrapolated blood kinetics showed similar effective half-lives for [⁶⁷Cu]Cu‑NODAGA-TATE and [¹⁷⁷Lu]Lu‑DOTA-TATE (~0.8 h) compared to the slower biphasic clearance of [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE (distribution: 2.15 h; clearance: 29.0 h). Organ dose projections revealed the highest doses in the urinary bladder and kidneys for all radioligands, with [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE yielding up to 60% higher kidney doses and a 2.3-fold higher total effective dose compared to [¹⁷⁷Lu]Lu‑DOTA-TATE.

Conclusion

The study confirms the potential of [⁶⁷Cu]Cu‑NODAGA-cLAB4‑TATE for SSTR2-positive tumors, with excellent tumor targeting and high-resolution SPECT imaging for monitoring therapy efficacy. Its compatibility with PET imaging using copper‑64 or copper‑61 adds versatility, highlighting its promise for radiocopper-based cancer theranostics. Further optimization could enhance tumor retention and imaging performance.

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