EJNMMI Radiopharmacy and Chemistry最新文献

Background

Automated dispensing systems (ADSs) for radiopharmaceuticals have been developed to reduce the radiation exposure of personnel, to improve the accuracy of the dispensed dose and to limit the microbiological contamination. However, before implementing such systems, validation according to various applicable guidelines is necessary to ensure safety and quality. Here we present the selection, validation and implementation of the PT459R2 from manufacturer Lynax s.r.o. as a guidance protocol for validation according to GMP and GRPP guidelines. Validation included linearity accuracy and precision of the internal scintillation detector for different isotopes and microbiological validation for aseptic procedures.

Results

The ADS can dispense accurate doses in the following linear range: 1000–10,000 MBq for lutetium-177, 20–74 MBq for zirconium-89, 100–1000 MBq for gallium-68 and 100–2000 MBq for fluorine-18. The maximum bias is 2.35% and the maximum coefficient of variation is 3.03% which meets the acceptance criteria of < 5%. Furthermore, the ADS does not affects the GMP class A environment in a laminar airflow cabinet and can dispense aseptically. In addition, radiation exposure is acceptable and data integrity is preserved.

Conclusion

The PT459R2 ADS met all the requirements from our performance qualification and is therefore suitable for daily routine use in our center. Our approach can be used as a guidance for PQ of an ADS in a Radiopharmacy according to GMP and GRPP guidelines.

Background

Multidrug resistance-associated protein 1 (MRP1), an energy-dependent efflux pump, is expressed widely in various tissues and contributes to many physiological and pathophysiological processes. 6-Bromo-7-[¹¹C]methylpurine ([¹¹C]7m6BP) is expected to be useful for the assessment of MRP1 activity in the human brain and lungs. However, the radiochemical yield (RCY) in the synthesis of [¹¹C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [¹¹C]CH₃I provided primarily the undesired isomer, 6-bromo-9-[¹¹C]methylpurine ([¹¹C]9m6BP). To increase the RCY of [¹¹C]7m6BP, we investigated conditions for improving the [¹¹C]7m6BP/[¹¹C]9m6BP selectivity of the methylation reaction.

Results

[¹¹C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [¹¹C]CH₃I in various solvents and at different temperatures in the presence of potassium carbonate for 5 min. Several less polar solvents, including tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (AcOEt) improved the [¹¹C]7m6BP/[¹¹C]9m6BP selectivity from 1:1 to 2:1, compared with the conventionally used solvents for the alkylation of 6-halopurines, acetone, acetonitrile, and N,N-dimethylformamide. However, a higher temperature (140 °C or 180 °C) was needed to progress the ¹¹C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [¹¹C]Methyl triflate ([¹¹C]CH₃OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The ¹¹C-methylation using [¹¹C]CH₃OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [¹¹C]CO₂, [¹¹C]7m6BP was produced with 2.3–2.6 GBq for THF, 2.7–3.3 GBq for AcOEt, and 2.8–3.9 GBq for 2-MeTHF at approximately 30 min after the end of bombardment (n = 3 per solvent). The isolated RCYs (decay corrected) for THF, 2-MeTHF, and AcOEt were 24–28%, 29–35%, and 22–31% (n = 3), respectively.

Conclusions

The use of THF, 2-MeTHF, and AcOEt improved the [¹¹C]7m6BP/[¹¹C]9m6BP selectivity in the methylation reaction, and the improved method provided [¹¹C]7m6BP with sufficient radioactivity for clinical use.

Background

In the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide.

Main body

Ac-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis. Multiple (methodological) challenges need to be overcome when working with Ac-225; as alpha-emission detection is time consuming and highly geometry dependent, a gamma co-emission is used, but has to be in equilibrium with the mother-nuclide. Because of the high impact of alpha emitters in vivo it is highly recommended to cross-calibrate the Ac-225 measurements for used quality control (QC) techniques (radio-TLC, HPLC, HP-Ge detector, and gamma counter). More strict health physics regulations apply, as Ac-225 has a high toxicity, thereby limiting practical handling and quantities used for QC analysis.

Conclusion

This overview focuses specifically on the practical and methodological challenges when working with Ac-225 labelled radiopharmaceuticals, and underlines the required infrastructure and (detection) methods for the (pre-)clinical application.

Background

Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [⁶⁸Ga]Ga-TacBOMB2 (⁶⁸Ga-DOTA-Pip-D-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Leu¹³-Thz¹⁴-NH₂).

Results

Unnatural amino acid substitutions were conducted for Gln⁷, Trp⁸, Ala⁹, Val¹⁰, Gly¹¹ and His¹², either alone or in combination. Out of 25 unnatural amino acid substitutions, tert-Leu¹⁰ (Tle¹⁰) and NMe-His¹² substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [⁶⁸Ga]Ga-TacBOMB2, the Tle¹⁰ and NMe-His¹² derived [⁶⁸Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (K_i = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection).

Conclusions

Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [⁶⁸Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.

Background

The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [⁶⁸Ga]Ga-PSMA-11. The purpose of this study was to investigate if [⁶⁸Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [⁶⁸Ga]Ga-PSMA-11.

Results

JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [⁶⁸Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [⁶⁸Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [⁶⁸Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [⁶⁸Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [⁶⁸Ga]Ga-PSMA-11 activity in these two organs during the first hour.

Conclusion

Biodistribution and micro-PET imaging of [⁶⁸Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [⁶⁸Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.

Background

We aimed to develop a publicly shared computational physiologically based pharmacokinetic (PBPK) model to reliably simulate and analyze radiopharmaceutical therapies (RPTs), including probing of hot-cold ligand competitions as well as alternative injection scenarios and drug designs, towards optimal therapies.

Results

To handle the complexity of PBPK models (over 150 differential equations), a scalable modeling notation called the “reaction graph” is introduced, enabling easy inclusion of various interactions. We refer to this as physiologically based radiopharmacokinetic (PBRPK) modeling, fine-tuned specifically for radiopharmaceuticals. As three important applications, we used our PBRPK model to (1) study the effect of competition between hot and cold species on delivered doses to tumors and organs at risk. In addition, (2) we evaluated an alternative paradigm of utilizing multi-bolus injections in RPTs instead of prevalent single injections. Finally, (3) we used PBRPK modeling to study the impact of varying albumin-binding affinities by ligands, and the implications for RPTs. We found that competition between labeled and unlabeled ligands can lead to non-linear relations between injected activity and the delivered dose to a particular organ, in the sense that doubling the injected activity does not necessarily result in a doubled dose delivered to a particular organ (a false intuition from external beam radiotherapy). In addition, we observed that fractionating injections can lead to a higher payload of dose delivery to organs, though not a differential dose delivery to the tumor. By contrast, we found out that increased albumin-binding affinities of the injected ligands can lead to such a differential effect in delivering more doses to tumors, and this can be attributed to several factors that PBRPK modeling allows us to probe.

Conclusions

Advanced computational PBRPK modeling enables simulation and analysis of a variety of intervention and drug design scenarios, towards more optimal delivery of RPTs.

Background

Triple-negative breast cancer (TNBC) is one of the most lethal malignant tumors among women, characterized by high invasiveness, high heterogeneity, and lack of specific therapeutic targets such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Trophoblast cell-surface antigen-2 (TROP-2) is a transmembrane glycoprotein over-expressed in 80% of TNBC patients and is associated with the occurrence, progress, and poor prognosis of TNBC. The TROP-2 targeted immunoPET imaging allows non-invasive quantification of the TROP-2 expression levels of tumors, which could help to screen beneficiaries most likely to respond to SG and predict the response. This study aimed to develop a ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody (NY003) for immunoPET and SPECT imaging, as well as radioimmunotherapy (RIT) in TROP-2 (+)TNBC tumor-bearing model. Based on the camelid antibody, we developed a TROP-2 targeted recombinant antibody NY003. NY003 was conjugated with DFO and DTPA for ⁸⁹Zr and ¹⁷⁷Lu radiolabelling, respectively. The theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 was evaluated through immunoPET, SPECT imaging, and RIT studies in the subcutaneous TROP-2 positive TNBC xenograft mice model.

Results

The high binding affinity of NY003 to TROP-2 was verified through ELISA. The radiochemical purity of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 exceeded 95% and remained stable within 144h p.i. in vitro. ImmunoPET and SPECT imaging showed the specific accumulation of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 in MDA-MB-231 tumors and gradually increased with the time tested, significantly higher than that in control groups (P < 0.05). The strongest anti-tumor efficacy was observed in the high-dose of [¹⁷⁷Lu]Lu-DTPA-NY003 group, followed by the low-dose group, the tumor growth was significantly suppressed by [¹⁷⁷Lu]Lu-DTPA-NY003, the tumor volumes of both high- and low-dose groups were smaller than the control groups (P < 0.05). Ex vivo biodistribution and histological staining verified the results of in vivo imaging and RIT studies.

Conclusion

As a drug platform for radiotheranostics, ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody NY003 could not only non-invasively screen the potential beneficiaries for optimizing SG ADC treatment but also suppressed the growth of TROP-2 positive TNBC tumors, strongly supporting the theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003.

Background

The ¹⁸F/¹⁹F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous ¹⁸F-labeling of peptides and proteins. However, the molar activity (A_m) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [¹⁸F]F⁻. To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct ¹⁸F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the ¹⁸F-labeled product from the phosphine oxide precursors, aiming to primarily increase A_m.

Results

Through a ¹⁹F-dehydrofluorination efficiency test, Cu(OAc)₂ was identified as the optimal oxidative metal salt, exhibiting a remarkable 100% conversion within one hour. Leveraging the straightforward separation of phosphine oxide precursors and phosphinic fluoride products, the A_m of an activated ester, [¹⁸F]4, sees an impressive nearly 15-fold increase compared to the ¹⁸F/¹⁹F-isotope exchange, with the same initial activity of [¹⁸F]F⁻. Furthermore, this Cu(II)-mediated ¹⁸F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of ¹⁸F-labeled water-soluble molecules under non-drying conditions.

Conclusions

The direct ¹⁸F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high A_m via Cu(II)-mediated oxidative addition and reductive elimination.

Background

There are only a handful of true theranostic matched pairs, and in particular the theranostic radiocopper trio ⁶¹Cu, ⁶⁴Cu and ⁶⁷Cu, for diagnosis and therapy respectively, is a very attractive candidate. In fact, the alternative of two imaging radionuclides with different half-lives is a clear advantage over other theranostic pairs, since it offers a better matching for the tracer biological and radionuclide physical half-lives. Due to the high availability of ⁶⁴Cu, its translation into the clinic is being successfully carried out, giving the example of the FDA approved radiopharmaceutical Detectnet (copper Cu 64 dotatate injection). However, a shorter-lived PET radionuclide such as ⁶¹Cu may as well be beneficial.

Results

Proton irradiation of enriched ⁶²Ni electrodeposited targets with a compact cyclotron produced the desired radionuclide via the ⁶²Ni(p,2n)⁶¹Cu nuclear reaction, leading to ⁶¹Cu activities of up to 20 GBq at end of bombardment and 8 GBq at end of purification. Furthermore, two purification methods are compared leading to comparable results regarding separation yield and product purity. Following the radiochemical separation, quality assessment of this product [⁶¹Cu]CuCl₂ solution proved radionuclidic purities (RNP) over 99.6% and apparent molar activities (AMA) of 260 GBq/µmol with the 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) chelator, end of purification corrected.

Conclusions

In the current article a comprehensive novel production method for the PET radionuclide ⁶¹Cu is presented, providing an alternative to the most popular production routes. Characterization of the [⁶¹Cu]CuCl₂ product showed both high RNP as well as high AMA, proving that the produced activity presented high quality regarding radiolabeling up to 9 h after end of purification. Furthermore, production scalability could be easily achieved by increasing the irradiation time.

Graphical abstract

Background

Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals.

Main body

This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals. These include the distinct characteristics of radiopharmaceuticals which require dedicated regulations, considering the impact of the variable complexity of radiopharmaceutical preparation, personnel requirements, manufacturing practices and quality assurance, regulatory authority interfaces, communication and training, as well as marketing authorisation procedures to ensure availability of radiopharmaceuticals. Finally, domestic and regional supply to ensure patient access via alternative regulatory pathways, including in-house production of radiopharmaceuticals, is described, and an outlook on regulatory challenges faced by new developments, such as the use of alpha emitters, is provided.

Conclusions

All these considerations are an outcome of a dedicated Technical Meeting organised by the IAEA in 2023 and represent the views and opinions of experts in the field, not those of any regulatory authorities.