an-automated-radiosynthesis-of-68gaga-fapi-46-for-routine-clinical-use

An Automated Radiosynthesis of [<sup>68</sup>Ga]Ga-FAPI-46 for Routine Clinical Use

[68Ga]Ga-FAPI-46 is a promising new tracer for the imaging of fibroblast activation protein (FAP) by positron emission tomography (PET). Labeled FAP ...

Sir Charles Gairdner Hospital

Molecular imaging provides an opportunity to study biological processes in vivo. Specific molecular 'probes' are labelled with radioactive tracers, and imaging is carried out using either PET or gamma-cameras. The imaging is quantitative, and therefore the activity of a specific biological process (e.g. metabolism or proliferation) can be numerically assessed, which may be important for prognosis or therapy monitoring. The use of molecular imaging may lead to the development of a 'molecular profile' of a disease, therefore facilitating individualization of therapy and rational treatment approaches. This review article summarizes the most commonly used molecular imaging agents and their role in lung and pleural diseases. This is a rapidly developing field as new targets and imaging probes are being developed and as their clinical roles are being established.

Novel molecular imaging in lung and pleural diseases.

Pancreatic carcinoma is known to demonstrate molecular features of hypoxia. The aim of this prospective pilot study is to analyze the hypoxia agent fluoromisonidazole (FMISO) using PET/CT in pancreatic carcinoma and to compare FMISO activity with glucose metabolism reflected by FDG.

Detection of hypoxia with 18F-fluoromisonidazole (18F-FMISO) PET/CT in suspected or proven pancreatic cancer.

We measured the excitation functions of (nat)Zn (p,x) reactions up to 17.6MeV, using the stacked-foils activation technique. High-purity natural zinc (and copper) foils were irradiated with proton beams generated by an 18MeV isochronous cyclotron. Activated foils were measured using high-purity Ge gamma spectroscopy to quantify the radionuclides (61)Cu, (66)Ga, (67)Ga, and (65)Zn produced from the reactions. Thick-target integral yields were also deduced from the measured excitation functions of the produced radioisotopes. These results were compared with the published literature and were found to be in good agreement with most reports, particularly those most recently compiled.

Excitation functions of (nat)Zn(p,x) nuclear reactions with proton beam energy below 18 MeV.

Malignant pleural mesothelioma (MPM) is a chemotherapy resistant tumor with a poor prognosis. Hypoxia is increasingly recognized as an important factor in tumor aggressiveness and cellular resistance to chemotherapy and radiation treatment. This prospective pilot study was performed with [F-18] fluoromisonidazole (FMISO) PET-CT to characterize hypoxia in patients with MPM.

Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT.

To evaluate the detection rate of positive choline PET-CT and its clinical role in assisting with management decisions and the correlation between positive choline PET-CT and clinical/pathological parameters in prostate cancer patients with biochemical relapse following radical prostatectomy.

A pilot study of the utility of choline PET-CT in prostate cancer biochemical relapse following radical prostatectomy.

Between 2009 and 2012,  Ga-somatostatin analogue PET-CT progressively replaced  In-octreotide scintigraphy for imaging neuroendocrine tumours in WA public hospitals due to published literature demonstrating improved diagnostic accuracy and increased availability. Despite significantly improved sensitivity and specificity,  Ga-somatostatin analogue PET is currently unfunded in Australia. This study sought to undertake cost analysis of the two modalities in a public hospital setting and to compare them with regard to patient factors such as imaging time and radiation dose.

 Ga-somatostatin analogue PET-CT: Analysis of costs and benefits in a public hospital setting.

Preliminary studies have reported promising results for the utility of gallium-68 (Ga-68) citrate positron emission tomography-computed tomography (PET-CT) for infection imaging. This technique offers reduced radiation dose to patients, shorter time between injection and imaging and reduced time for image acquisition compared to the 'gold standard' nuclear imaging technique: gallium-67 (Ga-67) citrate scintigraphy.

Comparison between gallium-68 citrate positron emission tomography-computed tomography and gallium-67 citrate scintigraphy for infection imaging.

The aim of this preclinical study was to directly compare [F]PSMA-1007 with both [Ga]Ga-PSMA-11 and [F]AlF-PSMA-11 in mice bearing PSMA-positive tumor xenografts. Uptake was assessed by PET/CT at 1, 2 and 4 h post-injection, and by ex vivo measurement after 4 h. [F]PSMA-1007 demonstrated the highest tumor uptake of the three tracers. The high uptake in bone for mice injected with [F]AlF-PSMA-11 suggested rapid in vivo decomposition. This was confirmed by an in vitro plasma stability study.

Direct in vivo comparison of [F]PSMA-1007 with [Ga]Ga-PSMA-11 and [F]AlF-PSMA-11 in mice bearing PSMA-expressing xenografts.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.

Since first becoming commercially available in 2018, the PET radiopharmaceutical [ F]PSMA-1007 has been used widely for the diagnosis and staging of prostate cancer. A pharmacopoeia monograph first became available in 2021, prescribing a radiochemical purity specification of >91%, based on analytical results from both TLC (for [ F]fluoride impurity alone) and HPLC (for all other  F-impurities). Though this monograph has provided clarity for the quality control testing of [ F]PSMA-1007, it prescribes a HPLC method using phosphate buffer mobile phase that may present a risk of precipitation of phosphate salts in the HPLC system. The method also requires specialised hardware not immediately available to all laboratories. This work describes the development of a simple, rapid reversed-phase HPLC method utilising 0.1 M ammonium formate mobile phase for the accurate assessment of both [ F]fluoride impurity and overall radiochemical purity in a single test. This method is especially useful for assessment of product stability over time. A more accurate TLC method for [ F]fluoride impurity is also described.

Development of a high-performance liquid chromatography method for rapid radiochemical purity measurement of [ F]PSMA-1007, a PET radiopharmaceutical for detection of prostate cancer.

Zr-labelled proteins are gaining importance in clinical research in a variety of diseases. To date, no clinical study has been reported that utilizes an automated approach for radiosynthesis of Zr-labelled radiopharmaceuticals. We aim to develop an automated method for the clinical production of Zr-labelled proteins and apply this method to Durvalumab, a monoclonal antibody targeting PD-L1 immune-checkpoint protein. PD-L1 expression is poorly understood and can be up-regulated over the course of chemo- and radiotherapy treatment. The ImmunoPET multicentre study aims to examine the dynamics of PD-L1 expression via Zr-Durvalumab PET imaging before, during, and after chemoradiotherapy. The developed automated technique will enable reproducible clinical production of [Zr]Zr-DFOSq-Durvalumab for this study at three different sites.

Article	Year
Novel molecular imaging in lung and pleural diseases. Respirology (Carlton, Vic.)\| PubMed ID: 21895862	2011
Detection of hypoxia with 18F-fluoromisonidazole (18F-FMISO) PET/CT in suspected or proven pancreatic cancer. Clinical nuclear medicine\| PubMed ID: 23242037	2013
Excitation functions of (nat)Zn(p,x) nuclear reactions with proton beam energy below 18 MeV. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine\| PubMed ID: 25108597	2014
Characterization of hypoxia in malignant pleural mesothelioma with FMISO PET-CT. Lung cancer (Amsterdam, Netherlands)\| PubMed ID: 26259878	2015
A pilot study of the utility of choline PET-CT in prostate cancer biochemical relapse following radical prostatectomy. Journal of medical imaging and radiation oncology\| PubMed ID: 27094471	2016
Ga-somatostatin analogue PET-CT: Analysis of costs and benefits in a public hospital setting. Journal of medical imaging and radiation oncology\| PubMed ID: 28714296	2018
Comparison between gallium-68 citrate positron emission tomography-computed tomography and gallium-67 citrate scintigraphy for infection imaging. Internal medicine journal\| PubMed ID: 30667165	2019
Direct in vivo comparison of [F]PSMA-1007 with [Ga]Ga-PSMA-11 and [F]AlF-PSMA-11 in mice bearing PSMA-expressing xenografts. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine\| PubMed ID: 32321698	2020
Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype. PLoS biology\| PubMed ID: 34520451	2021
Development of a high-performance liquid chromatography method for rapid radiochemical purity measurement of [ F]PSMA-1007, a PET radiopharmaceutical for detection of prostate cancer. Journal of labelled compounds & radiopharmaceuticals\| PubMed ID: 36649714	2023
Automated radiosynthesis of [Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo. Nuclear medicine and biology\| PubMed ID: 37224789	2023

Laurence Morandeau

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