EJNMMI Radiopharmacy and Chemistry最新文献

Background

With the next generation of Human Epidermal Growth Factor Receptor 2 (HER2) -targeting therapies, such as antibody–drug conjugates, showing benefit in “HER2 low” and even “HER2 ultralow” patients, the need for novel methods to quantify HER2 expression accurately becomes even more important for clinical decision making. A HER2 PET/CT imaging assessment could evaluate HER2 positive disease locations while improving patient care, reducing the need for invasive biopsies. A single-domain antibody (sdAb)-based PET tracer could combine the high specificity of sdAbs with short-lived radionuclides such as fluorine-18 (¹⁸F) and gallium-68 (⁶⁸Ga). SdAb-based PET tracers have clinically been used via a ⁶⁸Ga-chelator approach. However, the distribution of ⁶⁸Ga-labelled pharmaceuticals to peripheral PET centres is more challenging to organize due to the short half-life of ⁶⁸Ga, most certainly when the available activity is limited by a generator. Cyclotron produced ⁶⁸Ga has removed this limitation. Distribution of ¹⁸F-labelled pharmaceuticals remains less challenging due to its slightly longer half-life, and radiofluorination of sdAbs via N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) has shown to be a promising strategy for developing sdAb-based PET tracers. Although [¹⁸F]SFB automation has been reported, automating protein conjugation proves challenging. Herein we report the fully automated, cartridge-based production of [¹⁸F]FB-HER2 sdAb on a single synthesis module.

Results

[¹⁸F]FB-HER2 sdAb (> 6 GBq) was obtained after a fully automated production (95 min), with a RCP > 95%, apparent molar activity > 20 GBq/µmol and decay-corrected radiochemical yield (RCY d.c.) of 14 ± 2% (n = 4). Further upscaling amounted to production batches of 16 GBq with an apparent molar activity > 40 GBq/µmol and RCY d.c. of 8 ± 1% (n = 4). Ex vivo biodistribution and PET imaging showed specific HER2-positive tumour targeting and low kidney retention.

Conclusion

The [¹⁸F]FB-HER2 sdAb tracer was produced with clinically relevant activities using a fully automated production method. The automated production method was designed to ease the translation to the clinic and has the potential to be used not only in mono-centre but also multi-centre clinical trials with one central production site. [¹⁸F]FB-HER2 sdAb showed a favourable biodistribution pattern and could be a valuable alternative to ⁶⁸Ga-labelled sdAb-based PET tracers in the clinic.

Background

Pretargeted radioimmunotherapy of cancer has the potential to increase tumor specific uptake of activity when compared with conventional radioimmunotherapy. This is especially true in radioimmunotherapy with nuclides that exhibit a relatively short half-life. When administering antibody-based pretargeting molecules systemically, the antibodies often show a relatively slow clearance from the blood. Therefore, the use of a clearing agent is advantageous to remove unbound pretargeting molecules from the circulation, facilitating a reduction in the nonspecific radiation exposure to normal tissue while maximizing the dose delivered to the tumors.

Results

In the current study, two types of poly-L-lysine based clearing agents were produced for two different pretargeting systems: (strept)avidin/biotin and Tetrazine/Transcyclooctene. Poly-L-lysine was used as scaffold for production of clearing agents. The polymer is available in multiple sizes and can readily be modified with several functional groups, allowing different pretargeting strategies to be used. In vivo evaluation of the biotin-functionalized poly-L-lysine clearing agent, 110 repeating units, resulted in a decrease in blood concentration of the Iodine-125 labeled pretargeting agent of 50%, circa 23 h after injection, compared to controls. Two sizes, 68 and 143 repeating units, of the tetrazine-functionalized poly-L-lysine clearing agent were also evaluated, which at 23 h after injection decreased the blood concentration of the Iodine-125 labeled pretargeting agent to 58 and 38% respectively.

Conclusion

The straightforward synthesis of poly-L-lysine based clearing agents makes kit preparation possible and these agents show good potential for further evaluation, especially within the Tetrazine/Transcyclooctene pretargeting system where no liver or kidney accumulation was observed.

Background

The highly potent Auger electron emitter antimony-119 (¹¹⁹Sb) and the SPECT-isotope antimony-117 (¹¹⁷Sb) comprise a true theranostic pair particularly suitable for cancer theranostics. Harnessing this potential requires development of a chelator that can rapidly form a stable complex with radioactive antimony ions at the low concentrations typical of radiopharmaceutical preparations. Stable Sb(III) complexes of hydrotris(methimazolyl)borate (TMe) are known, prompting our investigation of this chelator. Additionally, the production of radioantimony was optimized and the SPECT imaging properties of ¹¹⁷Sb was investigated, in an attempt to move towards biomedical implementation of the theranostic isotope pair of antimony.

Results

A method for rapid and effective labelling of TMe using ¹¹⁷Sb was developed, yielding high radiochemical purities of 98.5 ± 2.7% and high radionuclidic purities exceeding 99%. Radiolabelling yielded an Sb(III) complex directly from the acidic Sb(V) solution. [^1XXSb]Sb-TMe in aqueous acidic solution showed high stability in the presence of cysteine, however, the stability of the radiocomplex at increased pH was significantly decreased. The production method of ¹¹⁷Sb was optimized, enabling a production yield of up to 19.6 MBq/µAh and the production of up to 564 MBq at end of bombardment, following irradiation of a thin ¹¹⁷Sn-enriched solid target. Preclinical SPECT/CT scanning of a mouse phantom containing purified ¹¹⁷Sb demonstrated excellent SPECT imaging properties of ¹¹⁷Sb with high spatial resolution comparable to that of technetium-99m.

Conclusion

We have explored the TMe chelator for complexation of radioantimony and devised a rapid chelation protocol suitable for the short half-life of ¹¹⁷Sb (T_1/2 = 2.8 h). [^1XXSb]Sb-TMe (^1XXSb = ¹¹⁷Sb, ^118mSb, ^120mSb and ¹²²Sb) demonstrated a high stability in presence of cysteine, although low stability was observed at pH > 4. We have achieved a production yield of ¹¹⁷Sb high enough for clinical applications and demonstrated the excellent SPECT-imaging properties of ¹¹⁷Sb. The results contribute valuable information for the development of suitable chelators for radioantimony and is a step further towards implementation of the antimony theranostic pair in biomedical applications.

Background

In recent years, the interest in Al[¹⁸F]F as a labeling agent for Positron Emission Tomography (PET) radiotracers has risen, as it allows for fast and efficient fluorine-18 labeling by harnessing chelation chemistry. The introduction of Restrained Complexing Agent (RESCA) as a chelator has also shown that chelator-based radiolabeling reactions can be performed in mild conditions, making the radiolabeling process attractively more facile than most conventional radiofluorination methods. The aim of the study was to establish optimized conditions for Al[¹⁸F]F labeling of Affibody molecules using RESCA as a complexing agent, using Z₀₉₅₉₁ and Z₀₁₈₅, two Affibody proteins targeting PDGFRβ and TNFα, respectively, as model compounds.

Results

The Al[¹⁸F]F labeling of RESCA-conjugated Z₀₉₅₉₁ was tested at different temperatures (rt to 60 °C) and with varying reaction times (12 to 60 min), and optimal conditions were then implemented on RESCA-Z₀₁₈₅. The optimized synthesis method was: 1.5–2.5 GBq of cyclotron produced fluorine-18 were trapped on a QMA cartridge and eluted with saline solution to react with 12 nmol of AlCl₃ and form Al[¹⁸F]F. The respective RESCA-conjugated Affibody molecule (14 nmol) in NaOAc solution was added to the Al[¹⁸F]F solution and left to react at 60 °C for 12 min. The mixture was purified on a NAP5 size exclusion column and then analyzed by HPLC. The entire process took approximately 35 min, was highly reproducible, indicating the efficiency and reliability of the method. The labeled compounds demonstrated retained biological function for their respective targets after purification.

Conclusions

We present a general and optimized method for Al[¹⁸F]F labeling of RESCA-conjugated Affibody molecules, which can be widely applied to this class of peptide-based imaging agents. Moreover, radiochemical yields were improved when the labeling was conducted at 37 °C or above. In vitro and in vivo assessment of the respective tracers was promising, showing retained binding capacity as well as moderate defluorination, which is usually regarded as a potential downside for RESCA-conjugated tracers.

Graphical abstract

Background

Radiopharmaceutical therapy (RPT) uses radionuclides that decay via one of three therapeutically relevant decay modes (alpha, beta, and internal conversion (IC) / Auger electron (AE) emission) to deliver short range, highly damaging radiation inside of diseased cells, maintaining localized dose distribution and sparing healthy cells. Antimony-119 (¹¹⁹Sb, t_1/2 = 38.19 h, EC = 100%) is one such IC/AE emitting radionuclide, previously limited to in silico computational investigation due to barriers in production, chemical separation, and chelation. A theranostic (therapeutic/diagnostic) pair can be formed with ¹¹⁹Sb’s radioisotopic imaging analogue ¹¹⁷Sb (t_1/2 = 2.80 h, E_γ = 158.6 keV, I_γ = 85.9%, β⁺ = 262.4 keV, I_β+ = 1.81%).

Results

Within, we report techniques for sustainable and cost-effective production of pre-clinical quality and quantity, radionuclidically pure ¹¹⁹Sb and ¹¹⁷Sb, novel low energy photon measurement techniques for ¹¹⁹Sb activity determination, and physical yields for various tin target isotopic enrichments and thicknesses using (p, n) and (d, n) nuclear reactions. Additionally, we present a two-column separation providing a radioantimony yield of 73.1% ± 6.9% (N = 3) and tin separation factor of (6.8 ± 5.5) x 10⁵ (N = 3). Apparent molar activity measurements for deuteron produced ¹¹⁷Sb using the chelator TREN-CAM were measured at 42.4 ± 25 MBq ¹¹⁷Sb/µmol (1.14 ± 0.68 mCi/µmol), and we recovered enriched ¹¹⁹Sn target material at a recycling efficiency of 80.2% ± 5.5% (N = 6) with losses of 11.6 mg ± 0.8 mg (N = 6) per production.

Conclusion

We report significant steps in overcoming barriers in ¹¹⁹Sb production, chemical isolation and purification, enriched target material recycling, and chelation, helping promote accessibility and application of this promising therapeutic radionuclide. We describe a method for ¹¹⁹Sb activity measurement using its low energy gamma (23.87 keV), negating the need for attenuation correction. Finally, we report the largest yet-measured ¹¹⁹Sb production yields using proton and deuteron irradiation of natural and enriched targets and radioisotopic purity > 99.8% at end of purification.

Background

In the central nervous system, type 2 vesicular monoamine transporters (VMAT2) are responsible for the reuptake of monoamines from synaptic junction back to pre-synaptic terminal vesicles. These transporters are functionally crucial as they reflect the integrity of monoamine neurons. D6-[¹⁸F]FP-(+)-DTBZ, a novel deuterated VMAT2 radioligand, has shown promise as a potential PET tracer for the diagnosis of Parkinson’s disease (PD). This study evaluates the biodistribution and dosimetry of D6-[¹⁸F]FP-(+)-DTBZ and includes a head-to-head comparison with its non-deuterated version, [¹⁸F]FP-(+)-DTBZ (AV-133), in healthy individuals and PD patients.

Results

The automated synthesis of D6-[¹⁸F]FP-(+)-DTBZ using the SPE method was accomplished in 35 min, yielding a high radiochemical purity (> 99%) and high radiochemical yields (35 ± 5%). The biodistribution and dosimetry study indicated an effective dose of 37.1 ± 7.2 μSv/MBq, with the liver receiving the highest radiation dose (289.6 ± 42.1 μGy/MBq), followed by pancreas (185.2 ± 29.1 μGy/MBq). Brain imaging with D6-[¹⁸F]FP-(+)-DTBZ exhibited a significantly increased uptake in VMAT2-rich regions, particularly the striatum. In a head-to-head comparison between [¹⁸F]FP-(+)-DTBZ and D6-[¹⁸F]FP-(+)-DTBZ, the latter exhibited approximately 15% higher SUVR in the caudate, putamen, and nucleus accumbens. Preliminary studies in PD patients showed a substantial reduction in VMAT2 uptake in the striatum, with the most pronounced decrease observed in the putamen (a 53% decline).

Conclusions

D6-[¹⁸F]FP-(+)-DTBZ is a safe and improved VMAT2-specific imaging agent, which may be suitable for diagnosing PD by evaluating changes in VMAT2 binding of monoamine neurons in the brain.

Trial registration Chinese Clinical Trial Registry, ChiCTR2200057218, Registered 16 August 2021, https://www.chictr.org.cn/bin/project/edit?pid=142725.

Background

Technetium-99 m-labelled macroaggregated human serum albumin ([99mTc]Tc-MAA) is commonly used for lung perfusion scintigraphy. The European Pharmacopoeia (Eu.Ph.) specifies thin-layer chromatography (TLC) as the only method to assess its radiochemical purity (RCP). Similarly, TLC is the sole method reported in the literature to evaluate the RCP of Gallium-68-labelled MAA [⁶⁸ Ga]Ga-MAA, recently introduced for lung perfusion PET/CT imaging. Since [⁶⁸ Ga]Ga-MAA is prepared from commercial kits originally designed for the preparation of [99mTc]Tc-MAA, it is essential to optimize and validate the preparation methods for [⁶⁸ Ga]Ga-MAA.

Results

We tested a novel, simplified method for the preparation of [⁶⁸ Ga]Ga-MAA that does not require organic solvents, prewash or final purification steps to remove radioactive impurities. We assessed the final product using radio-TLC, radio-UV-HPLC, and radio SDS-PAGE. Overall, our quality control (QC) method successfully detected [⁶⁸ Ga]Ga-MAA along with all potential impurities, including free Ga-68, [⁶⁸ Ga]Ga-HSA, unlabeled HSA, which may occur during labelling process and HEPES residual, a non-toxic but non-human-approved contaminant, used as buffer solution. We then applied our QC system to [⁶⁸ Ga]Ga-MAA prepared under different conditions (25°–40°–75°–95 °C), thus defining the optimal temperature for labelling. Scanning Electron Microscopy (SEM) analysis of the products obtained through our novel method confirmed that most [⁶⁸ Ga]Ga-MAA particles preserved the morphological structure and size distribution of unlabeled MAA, with a particle diameter range of 25–50 μm, assuring diagnostic efficacy.

Conclusions

We optimized a novel method to prepare [⁶⁸ Ga]Ga-MAA through a QC system capable of monitoring all impurities of the final products.

Background

²¹¹At-radiopharmaceuticals are currently the subject of growing studies for targeted alpha therapy of cancers, which leads to the widening of the scope of the targeting vectors, from small molecules to peptides and proteins. This has prompted, during the past decade, to a renewed interest in developing novel ²¹¹At-labelling approaches and novel prosthetic groups to address the diverse scenarios and to reach improved efficiency and robustness of procedures as well as an appropriate in vivo stability of the label.

Main body

Translated from the well-known (radio)iodine chemistry, the long preferred electrophilic astatodemetallation using trialkylaryltin precursors is now complemented by new approaches using electrophilic or nucleophilic At. Alternatives to the astatoaryl moiety have been proposed to improve labelling stability, and the range of prosthetic groups available to label proteins has expanded.

Conclusion

In this report, we cover the evolution of radiolabelling chemistry, from the initial strategies developed in the late 1970’s to the most recent findings.

Background

Gastroparesis (GP) is a prevalent sensorimotor disorder characterized by delayed gastric emptying without mechanical obstruction, posing significant diagnostic challenges. Gastric emptying scintigraphy (GES) is the gold standard for diagnosing GP. However, its accuracy can be compromised by many medications that affect gastric motility. This study evaluates the impact of medication reconciliation on the diagnostic accuracy of GES.

Results

A significant proportion of patients (75%) were on medications known to affect gastric motility. Recommendations for medication adjustments were communicated, with 30% non-adherence. Adjustments in GES interpretations were necessary for 20% of patients following comprehensive medication reviews. The involvement of radiopharmacists facilitated accurate diagnostic conclusions, underscoring the critical role of medication reconciliation in GES accuracy.

Conclusion

Medication reconciliation enhanced the accuracy of GES in diagnosing gastroparesis, emphasizing the need to integrate clinical pharmacy practices into nuclear medicine. This interdisciplinary approach not only improves diagnostic accuracy but also enhances patient safety, advocating for the adoption of such practices in the management of gastroparesis.