EJNMMI Radiopharmacy and Chemistry最新文献

Bacterial infections and antimicrobial resistance constitute significant threats to global human health, resulting in millions of fatalities annually. The development of innovative diagnostic agents is essential to facilitate precision medicine approaches in the battle against infectious diseases. Infection imaging using radiolabeled antimicrobial peptides (AMP) has emerged as a promising approach to detect bacterial infections. UBI(29–41), an AMP fragment, exhibits binding to bacterial cell membranes. Conjugated to chelators, UBI(29–41) has been labeled with radiometals such as ^99mTc or ⁶⁸Ga, and proven its ability to differentiate between sterile inflammation and infection with S. aureus by imaging. Due to its physical properties, ¹⁸F is more favorable for PET/CT imaging. As peptide labeling with ¹⁸F is challenging, we here implemented the Al¹⁸F labeling approach. This study aims to develop an optimized, fully automated, GMP-compliant process for radiolabeling of NOTA-conjugated UBI(29–41) with Al¹⁸F for PET/CT imaging of infections.

Optimized reaction conditions led to the establishment of a robust Al¹⁸Fcomplexation protocol, which was implemented on a SynChrom R&D module. The labeling reaction was carried out in an acidic medium (pH 4.0) at 105 °C for 15 min, followed by a two-step HPLC purification for 20 min. Optimization of reagent concentrations enabled an activity yield up to 10 ± 1 GBq, with a radiochemical yield of 24.2 ± 0.6% and an apparent molar activity of 45 ± 4 GBq/µmol at end of synthesis (EOS) (n = 3). The radiochemical purity was 96.6 ± 0.3% as determined by analytical HPLC, using UV absorption (220 nm). Quality control was successfully established using validated analytical procedures.

The developed GMP-compliant radiolabelling process yields reproducible results with sufficient activities for further translation and investigations of clinical PET/CT imaging using Al[¹⁸F]F-NOTA-UBI(29–41) in infectious diseases.

Background

Poly(ADP-ribose) polymerase (PARP) is an important therapeutic target in cancer treatment, and dynamic assessment of its expression level is essential for achieving precision therapy. Although ¹⁸F-labeled PARP-targeted radiotracers have demonstrated remarkable tumor-imaging capabilities in preclinical studies, their high lipophilicity leads to increased non-specific uptake in abdominal organs, which has severely hindered their clinical translation. Furthermore, while PET imaging provides superior resolution and sensitivity, its infrastructure and operational demands may limit widespread accessibility in certain regions. Therefore, the development of SPECT-based PARP radiotracers could offer a complementary approach, potentially expanding access to PARP imaging in a broader range of clinical settings. To provide a more affordable and accessible alternative to PET probes, hydrazinonicotinamide (HYNIC)-olaparib was radiolabeled with technetium-99m (^99mTc) and evaluated both in vitro and in vivo using the MDA-MB-453 breast cancer model.

Results

[^99mTc][Tc-HYNIC/EDDA]-olaparib exhibits a high radiochemical yield (> 90%), excellent radiochemical purity (> 90%), and good in vitro stability. The introduction of ethylenediamine-N, N’-diacetic acid (EDDA) and tricine facilitated the synthesis of ^99mTc complex, and improved the hydrophilicity (logP = 0.63 ± 0.25) of the probe as well, resulting in reduced the accumulation of radiation in the abdomen. In vitro results indicated that [^99mTc][Tc-HYNIC/EDDA]-olaparib could target PRAP-1 in MDA-MB-453 cells. In vivo experiments, micro SPECT/CT imaging provided clear visualization of MDA-MB-453 tumors with significant tumor-to-background distinction, and accumulation of [^99mTc][Tc-HYNIC/EDDA]-olaparib was quantified at 3.45 ± 0.17%ID/g at 1 h post intravenous injection.

Conclusion

These findings suggest that [^99mTc][Tc-HYNIC/EDDA]-olaparib holds great promise as a novel radiotracer for PARP imaging.

Background

Lutetium-177 (¹⁷⁷Lu) theranostics have revolutionized personalized cancer treatment, particularly with FDA-approved therapies like [¹⁷⁷Lu]Lu-DOTA-TATE for neuroendocrine tumors and [¹⁷⁷Lu]Lu-PSMA for prostate cancer. Despite growing clinical adoption, there is limited understanding of how different production variables affect radiochemical purity, especially when scaling to high activities for multi-patient batches. This study evaluates the impact of precursor sources, ¹⁷⁷Lu forms (carrier-added (C.A) vs. non- carrier-added (N.C.A)), and radiochemical concentration on product quality.

Results

We analyzed 355 clinical batches of [¹⁷⁷Lu]Lu-DOTA-TATE (n = 101), [¹⁷⁷Lu]Lu- PSMA-617 (n = 169), and [¹⁷⁷Lu]Lu-PSMA-I&T (n = 85) produced with standardized protocols using lutetium-177 from multiple suppliers in both carrier-added and non-carrier-added forms. All radiopharmaceuticals demonstrated consistently high yields (≥ 98%) and met release criteria regardless of starting materials. [¹⁷⁷Lu]Lu-DOTA-TATE and [¹⁷⁷Lu]Lu-PSMA-617 maintained radiochemical purity above 90% throughout 24 h, while [¹⁷⁷Lu]Lu-PSMA-I&T showed stability for 8 h but fell below specifications at 24 h. Negative correlations between bulk activity/concentration and radiochemical purity were observed across all preparations. The lutetium-177 products from various suppliers displayed notably distinct quality profiles. Some suppliers consistently provided higher radiochemical purities, irrespective of the carrier-added or non-carrier-added forms of lutetium-177. However, carrier- added formulations exhibited greater radiostability compared to non-carrier-added ones at elevated concentrations. Furthermore, differences in precursor quality among manufacturers were noted, with certain suppliers offering enhanced radiostability characteristics that may enhance product performance at high activity concentrations.

Conclusion

This comprehensive analysis reveals that hospital-based production can be automized resulting in high-quality and efficient multi-dose production. Small differences in radiochemical purity of ¹⁷⁷Lu -labeled theranostics depends on complex interactions between precursor source, ¹⁷⁷Lu supplier, and ¹⁷⁷Lu form, beyond simple activity-dependent radiolysis. These findings underscore the importance of optimizing production parameters for high- activity preparations and highlight the need to explore the various multifactorial variables that impact the quality of ¹⁷⁷Lu-theranostics.

Background

We describe here radiation nanomedicines for glioblastoma multiforme (GBM) composed of gold nanoparticles (AuNPs) that integrate the Auger electron-emitter, ¹⁹⁷Hg. [¹⁹⁷Hg]Hg-AuNPs were conjugated to anti-epidermal growth factor receptor (EGFR) panitumumab or were non-targeted. Our aim was to compare the cytotoxicity and DNA-damaging properties in vitro of panitumumab-[¹⁹⁷Hg]Hg-AuNPs and non-targeted [¹⁹⁷Hg]Hg-AuNPs on U251-Luc human GBM cells and estimate their cellular dosimetry. We further aimed to compare the biodistribution in vivo of panitumumab-[¹⁹⁷Hg]Hg-AuNPs and [¹⁹⁷Hg]Hg-AuNPs after convection-enhanced delivery (CED) in NRG mice with U251-Luc tumours in the brain and estimate the absorbed doses in the tumour and surrounding margins of healthy brain.

Results

[¹⁹⁷Hg]Hg-AuNPs (26.8 ± 6.4 nm) were produced with a radiochemical yield of 98 ± 1% by incorporating ¹⁹⁷Hg into the Turkevich synthesis method, forming a mercury-gold amalgam. Panitumumab-[¹⁹⁷Hg]Hg-AuNPs exhibited high affinity (K_D = 1.8 × 10^–9 mol/L) binding to EGFR-positive U251-Luc cells. The binding of panitumumab-[¹⁹⁷Hg]Hg-AuNPs to U251-Luc cells was 15-fold higher than [¹⁹⁷Hg]Hg-AuNPs, and internalization and nuclear uptake were 12-fold and 18-fold greater, respectively. Panitumumab-[¹⁹⁷Hg]Hg-AuNPs caused 84-fold more DNA double-strand breaks (DSBs) in U251-Luc cells than [¹⁹⁷Hg]Hg-AuNPs. Panitumumab-[¹⁹⁷Hg]Hg-AuNPs were ninefold more effective at reducing the clonogenic survival of U251-Luc cells than [¹⁹⁷Hg]Hg-AuNPs. Panitumumab-[¹⁹⁷Hg]Hg-AuNPs were twofold more cytotoxic than non-radioactive panitumumab-AuNPs (P = 0.04) and fivefold more cytotoxic than panitumumab (P = 0.01). The absorbed doses in the nucleus of U251-Luc cells treated in vitro with panitumumab-[¹⁹⁷Hg]Hg-AuNPs or [¹⁹⁷Hg]Hg-AuNPs were 8.8 ± 2.9 Gy and 0.6 ± 0.1 Gy, respectively. SPECT/CT imaging showed that panitumumab-[¹⁹⁷Hg]Hg-AuNPs and [¹⁹⁷Hg]Hg-AuNPs were strongly retained at the infusion site in the brain after CED up to 7 d in NRG mice with orthotopic U251-Luc tumours. Uptake of panitumumab-[¹⁹⁷Hg]Hg-AuNPs in the tumour-bearing right hemisphere [484.5% injected dose/g (%ID/g)] was 172-fold and 579-fold greater than in the healthy left hemisphere and cerebellum, respectively. The uptake of [¹⁹⁷Hg]Hg-AuNPs (423.9% ID/g) in the tumour-bearing right hemisphere was 85-fold and 64-fold higher than the left hemisphere and cerebellum, respectively. Most normal tissue uptake was < 1% ID/g, except for kidneys (9–20% ID/g), spleen (3.5–6.6% ID/g) and liver (0.6–3.3% ID/g). Dosimetry showed that 58% of the tumour received > 190 Gy for CED of 1.0 MBq of panitumumab-[¹⁹⁷Hg]Hg-AuNPs vs. 0.6