EJNMMI Radiopharmacy and Chemistry最新文献

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [¹⁷⁷Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [²²⁵Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.

Results

Cell binding and internalisation of [²²⁵Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [²²⁵Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [²²⁵Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [²²⁵Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [²²⁵Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.

Conclusion

[²²⁵Ac]Ac-DOTA-C595 was shown to target and induce a therapeutic effect in MUC1-CE expressing PDAC cells.

Background

Peptidic radiotracers are preferentially excreted through the kidneys, which often results in high persistent renal retention of radioactivity, limiting or even preventing therapeutic clinical translation of these radiotracers. Exendin-4, which targets the glucagon-like-peptide 1 receptor (GLP-1R) overexpressed in insulinomas and in congenital hyperinsulinism, is an example thereof. The use of the tripeptide MVK, which is readily cleaved between methionine and valine by neprilysin at the renal brush border membrane, already showed promising results in reducing kidney uptake as reported in the literature. Based on our previous findings we were interested how linker variants with multiple copies of the MV-motive influence renal washout of radiolabelled exendin-4.

Results

Three exendin-4 derivatives, carrying either one MVK, a MV-MVK or a MVK-MVK linker were synthesized and compared to a reference compound lacking a cleavable linker. In vivo results of a biodistribution in GLP-1R overexpressing tumour bearing mice at 24 h post-injection demonstrated a significant reduction (at least 57%) of renal retention of all ¹¹¹In-labeled exendin-4 compounds equipped with a cleavable linker compared to the reference compound. While the insertion of the single linker MVK led to a reduction in kidney uptake of 70%, the dual approach with the linker MV-MVK slightly, but not significantly enhanced this effect, with 77% reduction in kidney uptake compared to the reference. In vitro IC₅₀ and cell uptake studies were conducted and demonstrated that though the cleavable linkers negatively influenced the affinity towards the GLP-1R, cell uptake remained largely unaffected, except for the MV-MVK cleavable linker conjugate, which displayed lower cell uptake than the other compounds. Importantly, the tumour uptake in the biodistribution study was not significantly affected with 2.9, 2.5, 3.2 and 1.5% iA/g for radiolabelled Ex4, MVK-Ex4, MV-MVK-Ex4 and MVK-MVK-Ex4, respectively.

Conclusion

Cleavable linkers are highly efficient in reducing the radioactivity burden in the kidney. Though the dual linker approach using the instillation of MV-MVK or MVK-MVK between exendin-4 and the radiometal chelator did not significantly outperform the single cleavable linker MVK, further structural optimization or the combination of different cleavable linkers could be a stepping stone in reducing radiation-induced nephrotoxicity.

Background

Imaging of cell death can provide an early indication of treatment response in cancer. [^99mTc]Tc-Duramycin is a small-peptide SPECT tracer that recognizes both apoptotic and necrotic cells by binding to phosphatidylethanolamine present in the cell membrane. Preclinically, this tracer has shown to have favorable pharmacokinetics and selective tumor accumulation early after the onset of anticancer therapy. In this first-in-human study, we report the safety, biodistribution and internal radiation dosimetry of [^99mTc]Tc-Duramycin in healthy human volunteers.

Results

Six healthy volunteers (3 males, 3 females) were injected intravenously with [^99mTc]Tc-Duramycin (dose: 6 MBq/kg; 473 ± 36 MBq). [^99mTc]Tc-Duramycin was well tolerated in all subjects, with no serious adverse events reported. Following injection, a 30-min dynamic planar imaging of the abdomen was performed, and whole-body (WB) planar scans were acquired at 1, 2, 3, 6 and 23 h post-injection (PI), with SPECT acquisitions after each WB scan and one low-dose CT after the first SPECT. In vivo ^99mTc activities were determined from semi-quantitative analysis of the images, and time-activity curves were generated. Residence times were calculated from the dynamic and WB planar scans. The mean effective dose was 7.61 ± 0.75 µSv/MBq, with the kidneys receiving the highest absorbed dose (planar analysis: 43.82 ± 4.07 µGy/MBq, SPECT analysis: 19.72 ± 3.42 μGy/MBq), followed by liver and spleen. The median effective dose was 3.61 mSv (range, 2.85–4.14). The tracer cleared slowly from the blood (effective half-life of 2.0 ± 0.4 h) due to high plasma protein binding with < 5% free tracer 3 h PI. Excretion was almost exclusively renal.

Conclusion

[^99mTc]Tc-Duramycin demonstrated acceptable dosimetry (< 5 mSv) and a favorable safety profile. Due to slow blood clearance, optimal target-to-background ratios are expected 5 h PI. These data support the further assessment of [^99mTc]Tc-Duramycin for clinical treatment response evaluation.

Trial registration: NCT05177640, Registered April 30, 2021, https://clinicaltrials.gov/study/NCT05177640.

Background

The liver is a common site for metastatic disease for a variety of cancers, including colorectal cancer. Both primary and secondary liver tumors are supplied through the hepatic artery while the healthy liver is supplied by the portal vein. Transarterial radioembolization (TARE) using yttrium-90 glass or resin microspheres have shown promising results with reduced side-effects but have similar survival benefits as chemoembolization in patients with hepatocellular carcinoma (HCC). This highlights the need for new novel agents against HCC. Targeted alpha therapy (TAT) is highly potent treatment due to the short range (sparing adjacent normal tissue), and densely ionizing track (high linear energy transfer) of the emitted α-particles. The incorporation of α-particle-emitting radioisotopes into treatment of HCC has been extremely limited, with our recent publication pioneering the field of α-particle-emitting TARE (αTARE). This study focuses on an in-depth evaluation of the αTARE-agent [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® as an effective therapeutic agent against HCC regarding pharmacokinetics, dosimetry, stability, and therapeutic efficacy.

Results

[²²⁵Ac]Ac-DOTA-TDA was shown to be a highly stable with bench-top stability at ≥ 95% radiochemical purity (RCP) over a 3-day period and serum stability was ≥ 90% RCP over 5-days. The pharmacokinetic data showed retention in the tumor of [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® and clearance through the normal organs. In addition, the tumor and liver acted as suppliers of the free daughters, which accumulated in the kidneys supplied via the blood. The dose limiting organ was the liver, and the estimated maximum tolerable activity based on the rodents whole-body weight: 728–3641 Bq/g (male rat), 396–1982 Bq/g (male mouse), and 453–2263 Bq/g (female mouse), depending on an RBE-value (range 1–5). Furthermore, [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® showed significant improvement in survival for both the male and female mice (median survival 47-days) compared with controls (26-days untreated, and 33–35-days Lipiodol^® alone).

Conclusions

This study shows that [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® is a stable compound allowing for centralized manufacturing and distribution world-wide. Furthermore, the result of this study support the continue development of evaluation of the αTARE-agent [²²⁵Ac]Ac-DOTA-TDA-Lipiodol^® as a potential treatment option for treating hepatic tumors.

Background

Pancreatic ductal adenocarcinoma (PDAC) continues to be a malignancy with an unmet clinical demand. Development of radioimmunoconjugates which target cancer-specific receptors provides an opportunity for radioimmunotherapy of both metastatic and primary PDAC. In this study, we characterised the in vitro behaviour of a novel beta-emitting radioimmunoconjugate [¹⁷⁷Lu]Lu-DOTA-C595 as a therapeutic agent against PDAC. [¹⁷⁷Lu]Lu-DOTA-C595 is designed to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on most epithelial cancers, including PDAC.

Results

A series of in vitro experiments were performed on PDAC cell lines (PANC-1, CAPAN-1, BxPC-3 and AsPC-1) exhibiting strong to weak MUC1-CE expression. [¹⁷⁷Lu]Lu-DOTA-C595 bound to all cell lines relative to their expression of MUC1-CE. [¹⁷⁷Lu]Lu-DOTA-C595 was also rapidly internalised across all cell lines, with a maximum of 75.4% of activity internalised within the PANC-1 cell line at 48 h. The expression of γH2AX foci and clonogenic survival of PANC-1 and AsPC-1 cell lines after exposure to [¹⁷⁷Lu]Lu-DOTA-C595 were used to quantify the in vitro cytotoxicity of [¹⁷⁷Lu]Lu-DOTA-C595. At 1 h post treatment, the expression of γH2AX foci exceeded 97% in both cell lines. The expression of γH2AX foci continued to increase in PANC-1 cells at 24 h, although expression reduced in AsPC-1. Clonogenic assays showed a high level of cell kill induced by [¹⁷⁷Lu]Lu-DOTA-C595.

Conclusion

[¹⁷⁷Lu]Lu-DOTA-C595 has favourable in vitro characteristics to target and treat MUC1-CE positive PDAC. Further investigations to characterise the in vivo effects and potential value of [¹⁷⁷Lu]Lu-DOTA-C595 in other MUC1-CE expressing malignancies such as lung, ovarian and colorectal adenocarcinoma are warranted.

Background

The hypothetical concept of ‘macrocyclic cavity’ is largely employed as useful model to interpret the affinity of metal ions for the macrocyclic chelating ligand 2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (H₄DOTA). It Is hypothesized that a close matching between the size of the macrocyclic cavity and that of the metallic ion is a key parameter to ensure the high-yield formation of stable coordination metal-DOTA complex. This approach has become popular in the design of radiopharmaceuticals containing radiometals and H₄DOTA as chelating group.

Results

Based on X-ray structural data of metallic complexes formed by the ligand H₄DOTA upon coordination with a variety of metals, an elementary argument based on Euclidean geometry is presented here that questions the existence of the hypothetical ‘macrocyclic cavity’ within the chelator macrocycle. The geometrical analysis was applied to the complex formed by a Ga³⁺ ion coordinated to H₄DOTA as model compound.

Conclusions

Application of Euclidean geometry to calculate bond angles in the coordination complex of the ligand H₄DOTA with the Ga⁺³ ion, supposed to incorporate a hypothetical ‘macrocyclic cavity’, revealed that this conceptual entity has no physical reality and, therefore, cannot be considered a meaningful description of a stable structural arrangement for metallic radiopharmaceuticals.

Background

(S)-4-(3-¹⁸F-Fluoropropyl)-L-Glutamic Acid ([¹⁸F]FSPG) is a positron emission tomography (PET) tracer that specifically targets the cystine/glutamate antiporter (xc⁻), which is frequently overexpressed in cancer and several neurological disorders. Pilot studies examining the dosimetry and biodistribution of [¹⁸F]FSPG in healthy volunteers and tumor detection in patients with non-small cell lung cancer, hepatocellular carcinoma, and brain tumors showed promising results. In particular, low background uptake in the brain, lung, liver, and bowel was observed that further leads to excellent imaging contrasts of [¹⁸F]FSPG PET. However, reliable production-scale cGMP-compliant automated procedures for [¹⁸F]FSPG production are still lacking to further increase the utility and clinical adoption of this radiotracer. Herein, we report the optimized automated approaches to produce [¹⁸F]FSPG through two commercially available radiosynthesizers capable of supporting centralized and large-scale production for clinical use.

Results

Starting with activity levels of 60–85 GBq, the fully-automated process to produce [¹⁸F]FSPG took less than 45 min with average radiochemical yields of 22.56 ± 0.97% and 30.82 ± 1.60% (non-decay corrected) using TRACERlab™ FXFN and FASTlab™, respectively. The radiochemical purities were > 95% and the formulated [¹⁸F]FSPG solution was determined to be sterile and colorless with the pH of 6.5–7.5. No radiolysis of the product was observed up to 8 h after final batch formulation.

Conclusions

In summary, cGMP-compliant radiosyntheses and quality control of [¹⁸F]FSPG have been established on two commercially available synthesizers leveraging high activity concentration and radiochemical purity. While the clinical trials using [¹⁸F]FSPG PET are currently underway, the automated approaches reported herein will accelerate the clinical adoption of this radiotracer and warrant centralized and large-scale production of [¹⁸F]FSPG.

Background

A family of BF₂-chelated tetraaryl-azadipyrromethenes was developed as non-porphyrin photosensitizers for photodynamic therapy. Among the developed photosensitizers, ADPM06 exhibited excellent photochemical and photophysical properties. Molecular imaging is a useful tool for photodynamic therapy planning and monitoring. Radiolabeled photosensitizers can efficiently address photosensitizer biodistribution, providing helpful information for photodynamic therapy planning. To evaluate the biodistribution of ADPM06 and predict its pharmacokinetics on photodynamic therapy with light irradiation immediately after administration, we synthesized [¹⁸F]ADPM06 and evaluated its in vivo properties.

Results

[¹⁸F]ADPM06 was automatically synthesized by Lewis acid-assisted isotopic ¹⁸F-¹⁹F exchange using ADPM06 and tin (IV) chloride at room temperature for 10 min. Radiolabeling was carried out using 0.4 μmol of ADPM06 and 200 μmol of tin (IV) chloride. The radiosynthesis time was approximately 60 min, and the radiochemical purity was > 95% at the end of the synthesis. The decay-corrected radiochemical yield from [¹⁸F]F⁻ at the start of synthesis was 13 ± 2.7% (n = 5). In the biodistribution study of male ddY mice, radioactivity levels in the heart, lungs, liver, pancreas, spleen, kidney, small intestine, muscle, and brain gradually decreased over 120 min after the initial uptake. The mean radioactivity level in the thighbone was the highest among all organs investigated and increased for 120 min after injection. Upon co-injection with ADPM06, the radioactivity levels in the blood and brain significantly increased, whereas those in the heart, lung, liver, pancreas, kidney, small intestine, muscle, and thighbone of male ddY mice were not affected. In the metabolite analysis of the plasma at 30 min post-injection in female BALB/c-nu/nu mice, the percentage of radioactivity corresponding to [¹⁸F]ADPM06 was 76.3 ± 1.6% (n = 3). In a positron emission tomography study using MDA-MB-231-HTB-26 tumor-bearing mice (female BALB/c-nu/nu), radioactivity accumulated in the bone at a relatively high level and in the tumor at a moderate level for 60 min after injection.

Conclusions

We synthesized [¹⁸F]ADPM06 using an automated ¹⁸F-labeling synthesizer and evaluated the initial uptake and pharmacokinetics of ADPM06 using biodistribution of [¹⁸F]ADPM06 in mice to guide photodynamic therapy with light irradiation.

Background

The [¹⁷⁷Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [¹⁷⁷Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [¹⁷⁷Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [²²⁵Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [²²⁵Ac]Ac(NO₃)₃ and [¹⁷⁷Lu]LuCl₃. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for ^natLa-DOTA-JR11, ^natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [²²⁵Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [²²⁵Ac]Ac-DOTA-JR11 and [¹⁷⁷Lu]Lu-DOTA-JR11.

Results

[²²⁵Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [²²⁵Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [¹⁷⁷Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with ^natLa and ^natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [²²⁵Ac]Ac-DOTA-JR11 than [¹⁷⁷Lu]Lu-DOTA-JR11.

Conclusion

[²²⁵Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [¹⁷⁷Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [²²⁵Ac]Ac-DOTA-JR11.