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A large number of applications for fibroblast activation protein inhibitors (FAPI)-based PET agents have been evaluated in conditions ranging from cancer to non-malignant diseases such as myocardial infarction. In particular, 68Ga-FAPI-46 was reported to have a high specificity and affinity for FAP-expressing cells, a fast and high accumulation in tumor lesions/injuries together with a fast body clearance when investigated in vivo. Due to the increasing interest in the use of the agent both preclinically and clinically, we developed an automated synthesis for the production of 68Ga-FAPI-46 on a Trasis AiO platform. The new synthetic procedure, which included the processing of the generator eluate using a strong cation exchange resin and a final purification step through an HLB followed by a QMA cartridge, yielded 68Ga-FAPI-46 with high radiochemical purity (>98%) and apparent molar activity (271.1 ± 105.6 MBq/nmol). Additionally, the in vitro and in vivo properties of the product were assessed on glioblastoma cells and mouse model. Although developed for the preparation of 68Ga-FAPI-46 for preclinical use, our method can be adapted for clinical production as a reliable alternative to the manual (i.e., cold kit) or modular systems preparations already described in the literature.

68Ga-radionuclide has gained importance due to its availability via 68Ge/68Ga generator or cyclotron production, therefore increasing the number of 68Ga-based PET radiopharmaceuticals available in clinical practice. [68Ga]Ga-citrate PET has been shown to be prominent for detection of inflammation/infection of the musculoskeletal, gastrointestinal, respiratory, and cardiovascular systems. Automation and comparison between conventional and microfluidic production of [68Ga]Ga-citrate was performed using miniAllInOne® (Trasis) and iMiDEV™ (PMB-Alcen) synthetic modules. Fully automated procedures were elaborated for cGMP production of tracer. In order to facilitate the tracer approval as a radiopharmaceutical for clinical use, a new method for radiochemical identity determination by HPLC analysis to complement standard TLC radiochemical purity measurement was developed. The results showed higher radiochemical yields when using MCX cartridge on the conventional module mAIO®, while a PS-H+ cation exchanger was shown to be preferred for integration into the microfluidic cassette of iMiDEV™ module. In this study, the fully automated radiosynthesis of [68Ga]Ga-citrate using different synthesizers demonstrated reliable and reproducible radiochemical yields. In order to demonstrate the applicability of [68Ga]Ga-citrate, in vitro and in vivo studies were performed showing similar characteristics of the tracer obtained using macro- and microfluidic ways of production.

Purpose Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer’s disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18 F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([ 18 F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [ 18 F]FSW-100. Methods Process validation of [ 18 F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [ 18 F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans. Results Three consecutive validation runs of the automated radiosynthesis gave [ 18 F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [ 18 F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18 F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [ 18 F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific. Conclusion These results support the clinical utility of [ 18 F]FSW-100 for in vivo imaging of HDAC6 in the brain.

σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown.

FAP-targeted radiopharmaceuticals represent a breakthrough in cancer imaging and a viable option for therapeutic applications. OncoFAP is an ultra-high-affinity ligand of FAP with a dissociation constant of 680 pM. OncoFAP has been recently discovered and clinically validated for PET imaging procedures in patients with solid malignancies. While more and more clinical validation is becoming available, the need for scalable and robust procedures for the preparation of this new class of radiopharmaceuticals continues to increase. In this article, we present the development of automated radiolabeling procedures for the preparation of OncoFAP-based radiopharmaceuticals for cancer imaging and therapy. A new series of [68Ga]Ga-OncoFAP, [177Lu]Lu-OncoFAP and [18F]AlF-OncoFAP was produced with high radiochemical yields. Chemical and biochemical characterization after radiolabeling confirmed its excellent stability, retention of high affinity for FAP and absence of radiolysis by-products. The in vivo biodistribution of [18F]AlF-NOTA-OncoFAP, a candidate for PET imaging procedures in patients, was assessed in mice bearing FAP-positive solid tumors. The product showed rapid accumulation in solid tumors, with an average of 6.6% ID/g one hour after systemic administration and excellent tumor-to-healthy organs ratio. We have developed simple, quick, safe and robust synthetic procedures for the preparation of theranostic OncoFAP-compounds based on Gallium-68, Lutetium-177 and Fluorine-18 using the commercially available FASTlab synthesis module.

There is limited information on utilizing commercially supplied [ 18 F]Fluoride from an off-site cyclotron for the synthesis of radiopharmaceuticals. This study explored the production of the PET hypoxia marker [ 18 F]FMISO, using the Scintomics® GRP module and distantly produced [ 18 F]Fluoride, which lacks published data. A radiochemical yield of 27.4 ± 3.6% ( n  = 5) and high radiochemical purity were achieved in synthesis time of 48 min. The [ 18 F]FMISO met all Ph. Eur. standards, demonstrating the consistency and reliability of the module in generating a clinical-grade radiopharmaceutical using off-site produced [ 18 F]Fluoride, but available patient doses were severely limited.

Background Prostate-specific membrane antigen (PSMA) is frequently overexpressed and upregulated in prostate cancer. To date, various 18 F- and 68 Ga-labeled urea-based radiotracers for PET imaging of PSMA have been developed and entered clinical trials. Here, we describe an automated synthesis of [ 18 F]DCFPyL via direct radiofluorination and validation in preclinical models of prostate cancer. Methods [ 18 F]DCFPyL was synthesized via direct nucleophilic heteroaromatic substitution reaction in a single reactor TRACERlab FX FN automated synthesis unit. Radiopharmacological evaluation of [ 18 F]DCFPyL involved internalization experiments, dynamic PET imaging in LNCaP (PSMA+) and PC3 (PSMA−) tumor-bearing BALB/c nude mice, biodistribution studies, and metabolic profiling. In addition, reversible two-tissue compartmental model analysis was used to quantify pharmacokinetics of [ 18 F]DCFPyL in LNCaP and PC3 tumor models. Results Automated radiosynthesis afforded radiotracer [ 18 F]DCFPyL in decay-corrected radiochemical yields of 23 ± 5 % ( n  = 10) within 55 min, including HPLC purification. Dynamic PET analysis revealed rapid and high uptake of radioactivity (SUV 5min 0.95) in LNCaP tumors which increased over time (SUV 60min 1.1). Radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive DCFPyL (SUV 60min 0.22). The muscle as reference tissue showed rapid and continuous clearance over time (SUV 60min 0.06). Fast blood clearance of radioactivity resulted in tumor-blood ratios of 1.0 after 10 min and 8.3 after 60 min. PC3 tumors also showed continuous clearance of radioactivity over time (SUV 60min 0.11). Kinetic analysis of PET data revealed the two-tissue compartmental model as best fit with K 1  = 0.12, k 2  = 0.18, k 3  = 0.08, and k 4  = 0.004 min −1 , confirming molecular trapping of [ 18 F]DCFPyL in PSMA+ LNCaP cells. Conclusions [ 18 F]DCFPyL can be prepared for clinical applications simply and in good radiochemical yields via a direct radiofluorination synthesis route in a single reactor automated synthesis unit. Radiopharmacological evaluation of [ 18 F]DCFPyL confirmed high PSMA-mediated tumor uptake combined with superior clearance parameters. Compartmental model analysis points to a two-step molecular trapping mechanism based on PSMA binding and subsequent internalization leading to retention of radioactivity in PSMA+ LNCaP tumors.

Purpose A reliable and routine process to introduce a new 18 F-labeled dimeric RGD-peptide tracer ([ 18 F]FPP(RGD) 2 ) for noninvasive imaging of α v β 3 expression in tumors needed to be developed so the tracer could be evaluated for the first time in man. Clinical-grade [ 18 F]FPP(RGD) 2 was screened in mouse prior to our first pilot study in human. Procedures [ 18 F]FPP(RGD) 2 was synthesized by coupling 4-nitrophenyl-2-[ 18 F]fluoropropionate ([ 18 F]NPE) with the dimeric RGD-peptide (PEG 3 -c(RGDyK) 2 ). Imaging studies with [ 18 F]FPP(RGD) 2 in normal mice and a healthy human volunteer were carried out using small animal and clinical PET scanners, respectively. Results Through optimization of each radiosynthetic step, [ 18 F]FPP(RGD) 2 was obtained with RCYs of 16.9 ± 2.7% ( n  = 8, EOB) and specific radioactivity of 114 ± 72 GBq/μmol (3.08 ± 1.95 Ci/μmol; n  = 8, EOB) after 170 min of radiosynthesis. In our mouse studies, high radioactivity uptake was only observed in the kidneys and bladder with the clinical-grade tracer. Favorable [ 18 F]FPP(RGD) 2 biodistribution in human studies, with low background signal in the head, neck, and thorax, showed the potential applications of this RGD-peptide tracer for detecting and monitoring tumor growth and metastasis. Conclusions A reliable, routine, and automated radiosynthesis of clinical-grade [ 18 F]FPP(RGD) 2 was established. PET imaging in a healthy human volunteer illustrates that [ 18 F]FPP(RGD) 2 possesses desirable pharmacokinetic properties for clinical noninvasive imaging of α v β 3 expression. Further imaging studies using [ 18 F]FPP(RGD) 2 in patient volunteers are now under active investigation.

Background The rapidly increasing clinical demand for 68 Ga-labelled radiopharmaceuticals continues to challenge current production capacities, particularly in high-throughput nuclear medicine departments. Although dual-generator concepts have previously been explored, all reported approaches to date have required either pre-purification, fractionated elution, or additional cartridge-based concentration steps, which add complexity and limit routine clinical implementation. In the present study, we report for the first time a fully automated, GMP-compliant synthesis protocol using two iThemba 68 Ge/ 68 Ga generators connected in series on a standard EasyOne module applicable to three clinically relevant tracers. We successfully established robust GMP production of [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-FAPI-46, and [ 68 Ga]Ga-PentixaFor without any pre-purification or fractional elution. A key mechanistic finding of this work is the critical role of direct ascorbic acid addition to the reaction medium, which effectively suppresses radiolysis and metal-ion interference under high-activity conditions. Results We established a Good Manufacturing Practice (GMP)-compliant, fully automated synthesis of [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-Pentixafor, and [ 68 Ga]Ga-FAPI-46 using two 68 Ge/ 68 Ga iThemba generators connected in series, of which the older generator is replaced with a new one every 6 months. This configuration enabled elution of maximum activity of 3750 MBq and minimum activity of 2345 MBq, exceeding the elution activity achieved with a single generator by 2300 and 901 MBq respectively. The corrected yield of the labelled products was 91 ± 5% (72 ± 5% non-decay corrected). The additional activity of the labeled products obtained through the two generator configuration enables the examination of 2–4 additional patients per batch and thus resulting in significant cost savings. The direct addition of ascorbic acid to the reaction medium was essential, as it suppressed radiolysis and minimized the impact of metallic impurities. This innovation enabled reproducible labeling without pre-purification, which has not previously been demonstrated with SnO 2 -based generators. Conclusions Dual-generator elution on the EasyOne module without modification of Trasis single-use cassettes provides a robust and scalable approach for high-yield production of 68 Ga radiopharmaceuticals. The integration of series-connected iThemba generators with in-situ radiolysis control by ascorbic acid ensures consistent GMP-compliant synthesis of [ 68 Ga]Ga-DOTATATE, [ 68 Ga]Ga-Pentixafor, and [ 68 Ga]Ga-FAPI-46. This method improves production efficiency, reduces costs, and expands clinical accessibility.

BackgroundThe recent development of quinoline-based radiotracers, which act as fibroblast activation protein inhibitors (FAPIs), has shown promising preclinical and clinical advantages. [68Ga]Ga-FAPI-46 is a new radiotracer for in vivo detection of the fibroblast activation protein by positron emission tomography (PET). Recently, the automated synthesis of [68Ga]Ga-FAPI-46 was reported based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge.Our aim was to simplify the synthesis and shorten the automated synthesis of [68Ga]Ga-FAPI-46 to make it accessible and thus even more attractive to a broader clinical and scientific community.ResultsWe developed and evaluated the GMP compliant automatic synthesis of [68Ga]Ga-FAPI-46 using two different 68Ge/68Ga generators (an Eckert & Ziegler, GalliaPharm generator, 1.85 GBq/50 mCi and an iThemba generator, 1.85 GBq/50 mCi) Somerset West, South Africa) and three different commercial and customized systems: the EasyOne module from Trasis; the GaSy module from Synthra with a customized synthesis template and a customized single use cassette. Additionally, the automatic synthesis of [68Ga]Ga-FAPI-46 was established on a GallElut synthesis module from Scintomics with fixed tubing.ConclusionsIndependent of the synthesis modules or the generators employed we were able to complete the synthesis of [68Ga]Ga-FAPI-46 in 12 min including the process of purification and formulation. In all cases, the final products showed more than 99.5% chemical purity and the radiochemical yield reached around 92.5% (decay corrected). All quality control parameters (e.g. sterility, stability and radiochemical purity) were conform to the European Pharmacopoeia.