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Background: The orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of 18F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective antagonist JH112. Results: Computational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a–1f, in vitro OXR binding studies confirmed the molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a–f, ranging from 0.69 to 2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of boroxine precursors allowed for a shortened reaction time of 5 min to provide the non-selective OXR ligand [18F]1c and its selective OX1R congener [18F]1f in activity yields of 14% and 22%, respectively, within a total synthesis time of 52–76 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma protein binding of 66% and 77%, respectively. Dynamic PET imaging in rats showed similar brain uptake of [18F]1c (0.17%ID/g) and [18F]1f (0.15%ID/g). However, preinjection of suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporine A to study the role of P-glycoprotein (P-gp) in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p < 0.05) and had no effect on the transport of 1f, indicating that P-gp does not play a relevant role in brain accumulation of [18F]1c and [18F]1f in vivo. Conclusions: The in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging. [ABSTRACT FROM AUTHOR]

Abstract Background The orexin receptor (OXR) plays a role in drug addiction and is aberrantly expressed in colorectal tumors. Subtype-selective OXR PET ligands suitable for in vivo use have not yet been reported. This work reports the development of 18F-labeled OXR PET ligand candidates derived from the OXR antagonist suvorexant and the OX1R-selective antagonist JH112. Results Computational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a–1f, in vitro OXR binding studies confirmed the molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a–f, ranging from 0.69 to 2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of boroxine precursors allowed for a shortened reaction time of 5 min to provide the non-selective OXR ligand [18F]1c and its selective OX1R congener [18F]1f in activity yields of 14% and 22%, respectively, within a total synthesis time of 52–76 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma protein binding of 66% and 77%, respectively. Dynamic PET imaging in rats showed similar brain uptake of [18F]1c (0.17%ID/g) and [18F]1f (0.15%ID/g). However, preinjection of suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporine A to study the role of P-glycoprotein (P-gp) in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p

Purpose: To describe the pharmacokinetic properties of the [18F]fluoro-polyethylene glycol(PEG)-folate radiotracer in PET/CT imaging of patients with advanced stage epithelial ovarian cancer (EOC). Procedures: In five patients with advanced EOC (FIGO stage IIIB/IIIC, Fédération Internationale de Gynécologie et d'Obstétrique), a 90-min dynamic PET acquisition of the pelvis was performed directly after i.v. administration of 185 MBq [18F]fluoro-PEG6-folate. Arterial blood samples collected at nineteen timepoints were used to determine the plasma input function. A static volume of interest (VOI) for included tumor lesions was drawn manually on the PET images. Modelling was performed using PMOD software. Three different models (a 1-tissue compartment model (1T2k) and two 2-tissue compartment models, irreversible (2T3k) and reversible (2T4k)) were compared in goodness of fit with the time activity curves by means of the Akaike information criterion. Results: The pharmacokinetic analysis in the pelvic area has proven to be much more challenging than expected. Only four out of 22 tumor lesions in five patients were considered suitable to perform modelling on. The remaining tumor lesions were inapt due to either low tracer uptake, small size, proximity to other [18F]fluoro-PEG6-folate -avid structures and/or displacement by abdominal organ motion in the dynamic scan. Data from the four analyzed tumor lesions suggest that the irreversible 2T3k may best describe the pharmacokinetics. All 22 lesions were immunohistochemically stained positive for the folate receptor alpha (FRα) after resection. Conclusion: Performing pharmacokinetic analysis in the abdominal pelvic region is very challenging. This brief article describes the challenges and pitfalls in pharmacokinetic analysis of a tracer with high physiological accumulation in the intestines, in case of lesions of limited size in the abdominal pelvic area. [ABSTRACT FROM AUTHOR]

One of the key strategies for radiochemical research facilities is the automation of synthesis processes. Unnecessary manual operations increase the radiation exposure of personnel, while simultaneously threatening the reliability of syntheses. We have previously reported an affordable open‐source system comprising 3D‐printed continuous flow reactors, a custom syringe pump, and a pressure regulator that can be used to perform radiofluorinations. In this paper, we address additional essential processes that are needed for radiotracer development and synthesis, with the aim of making laboratory work safer and research more efficient. We have designed and evaluated a fully automated system for rapidly and effectively processing and drying aqueous [18F]fluoride that can be directly connected to the cyclotron. This process relies on triflyl fluoride gas generation and allows nucleophilic [18F]fluoride to be prepared safely in a hotcell within 10 min and an activity recovery of 91.7 ± 1.6% (n = 5). Owing to the need for convenient radiofluorinated prosthetic ligands, we have adapted our continuous flow system to produce [18F]fluoroethyl tosylate (FEOTs) and [18F]fluoroethyl triflate (FEOTf), prosthetic groups that are widely used for late‐stage fluoroethylation of PET tracers. The processes as well as the radiolabeling of different groups are compared and comprehensively discussed. Having a method providing [18F]fluoroethyl tosylate (FEOTs) as well as [18F]fluoroethyl triflate (FEOTf) quickly and highly efficiently is beneficial for radiochemical research. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a powerful tool for imaging biological processes in the central nervous system (CNS). Designing PET radiotracers capable of crossing the blood–brain barrier (BBB) remains a major challenge. In addition to being brain‐penetrant, a quantifiable CNS PET radiotracer must have high target affinity and selectivity, appropriate pharmacokinetics, minimal non‐specific binding, negligible radiometabolites in the brain, and generally must be amenable to labeling with carbon‐11 (11C) or fluorine‐18 (18F). This review aims to give an overview of some of the critical physicochemical and biochemical contributors specific for CNS PET radiotracer design and how they can differ from pharmaceutical drug development, including in vitro assays, in silico predictions, and in vivo studies, with examples for how such methods can be implemented to optimize brain uptake of radiotracers based on experiences from our neuroimaging program. [ABSTRACT FROM AUTHOR]

Abstract New modes of production and supply of short-lived radioisotopes using accelerators are becoming attractive alternatives to the use of nuclear reactors. In this study, the use of a compact accelerator neutron source (CANS) was implemented to explore the production of 99mTc and 101Tc. Irradiations were performed with neutrons generated from a 16.5 MeV cyclotron utilising the 18O(p, n)18F reaction during routine 18F-fluorodeoxyglucose (FDG) production in a commercial radiopharmacy. Natural molybdenum targets in metal form were employed for the production of several Tc isotopes interest via (n, γ) reactions on 98Mo and 100Mo. The production of 99mTc and 101Tc under these conditions is considered and discussed.

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [18F]Favipiravir in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [18F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [18F]Favipiravir in vivo. The [18F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET. [ABSTRACT FROM AUTHOR]

Antibody-based dual-modality (PET/fluorescence) imaging enables both presurgery antigen-specific immuno-PET for noninvasive whole-body evaluation and intraoperative fluorescence for visualization of superficial tissue layers for image-guided surgery. Methods: We developed a universal dual-modality linker (DML) that facilitates site-specific conjugation to a cysteine residue-bearing antibody fragment, introduction of a commercially available fluorescent dye (via an amine-reactive prosthetic group), and rapid and efficient radiolabeling via click chemistry with 18F-labeled trans-cyclooctene (18F-TCO). To generate a dual-modality antibody fragment-based imaging agent, the DML was labeled with the far-red dye sulfonate cyanine 5 (sCy5), site-specifically conjugated to the C-terminal cysteine of the anti-prostate stem cell antigen (PSCA) cys-diabody A2, and subsequently radiolabeled by click chemistry with 18F-TCO. The new imaging probe was evaluated in a human PSCA-positive prostate cancer xenograft model by sequential immuno-PET and optical imaging. Uptake in target tissues was confirmed by ex vivo biodistribution. Results: We successfully synthesized a DML for conjugation of a fluorescent dye and 18F. The anti-PSCA cys-diabody A2 was site-specifically conjugated with either DML or sCy5 and radiolabeled via click chemistry with 18F-TCO. Immuno-PET imaging confirmed in vivo antigen-specific targeting of prostate cancer xenografts as early as 1 h after injection. Rapid renal clearance of the 50-kDa antibody fragment enables same-day imaging. Optical imaging showed antigen-specific fluorescent signal in PSCA-positive xenografts and high contrast to surrounding tissue and PSCA-negative xenografts. Conclusion: The DML enables site-specific conjugation away from the antigen-binding site of antibody fragments, with a controlled linker-to-protein ratio, and combines signaling moieties for 2 imaging systems into 1 molecule. Dual-modality imaging could provide both noninvasive whole-body imaging with organ-level biodistribution and fluorescence image-guided identification of tumor margins during surgery.

PurposeMetabolic imaging using [18F]FDG is the current standard for clinical PET; however, some malignancies (e.g., indolent lymphomas) show low avidity for FDG. The majority of B cell lymphomas express CD20, making it a valuable target both for antibody-based therapy and imaging. We previously developed PET tracers based on the humanised anti-CD20 antibody obinutuzumab (GA101). Preclinical studies showed that the smallest bivalent fragment, the cys-diabody (GAcDb, 54.5 kDa) with a peak uptake at 1-2 h post-injection and a biological half-life of 2-5 h, is compatible with short-lived positron emitters such as fluorine-18 (18F, t1/2 110 min), enabling same-day imaging.MethodsGAcDb was radiolabeled using amine-reactive N-succinimidyl 4-[18F]-fluorobenzoate ([18F]SFB), or thiol-reactive N-[2-(4-[18F]-fluorobenzamido)ethyl]maleimide ([18F]FBEM) for site-specific conjugation to C-terminal cysteine residues. Both tracers were used for immunoPET imaging of the B cell compartment in human CD20 transgenic mice (hCD20TM). [18F]FB-GAcDb immunoPET was further evaluated in a disseminated lymphoma (A20-hCD20) syngeneic for hCD20TM and compared to [18F]FDG PET. Tracer uptake was confirmed by ex vivo biodistribution.ResultsThe GAcDb was successfully 18F-radiolabeled using two different conjugation methods resulting in similar specific activities and without impairing immunoreactivity. Both tracers ([18F]FB-GAcDb and [18F]FBEM-GAcDb) specifically target human CD20-expressing B cells in transgenic mice. Fast blood clearance results in high contrast PET images as early as 1 h post injection enabling same-day imaging. [18F]FB-GAcDb immunoPET detects disseminated lymphoma disease in the context of normal tissue expression of hCD20, with comparable sensitivity as [18F]FDG PET but with added specificity for the therapeutic target.Conclusions[18F]FB-GAcDb and [18F]FBEM-GAcDb could monitor normal B cells and B cell malignancies non-invasively and quantitatively in vivo. In contrast to [18F]FDG PET, immunoPET provides not only information about the extent of disease but also about presence and localisation of the therapeutic target.

New modes of production and supply of short-lived radioisotopes using accelerators are becoming attractive alternatives to the use of nuclear reactors. In this study, the use of a compact accelerator neutron source (CANS) was implemented to explore the production of 99mTc and 101Tc. Irradiations were performed with neutrons generated from a 16.5 MeV cyclotron utilising the 18O(p, n)18F reaction during routine 18F-fluorodeoxyglucose (FDG) production in a commercial radiopharmacy. Natural molybdenum targets in metal form were employed for the production of several Tc isotopes interest via (n, γ) reactions on 98Mo and 100Mo. The production of 99mTc and 101Tc under these conditions is considered and discussed. [ABSTRACT FROM AUTHOR]

Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional molecules/nanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the subsequent treatment planning procedure of BNCT. Borono phenylalanine (BPA), recognized by the l-type amino acid transporter, can cross the blood-brain barrier and be accumulated in gliomas. The radiofluoro BNCT agents are reviewed by considering (1) less cytotoxicity, (2) diagnosing and therapeutic purposes, (3) aqueous solubility and extraction route, as well as (4), the trifluoroborate effect. A trifluoroborate-containing amino acid such as fluoroboronotyrosine (FBY) represents an example with both functionalities of imaging and therapeutics. Comparing with the insignificant cytotoxicity of clinical BPA with IC50 > 500 μM, FBY also shows minute toxicity with IC50 > 500 μM. [18F]FBY is a potential diagnostic agent for its tumor to normal accumulation (T/N) ratio, which ranges from 2.3 to 24.5 from positron emission tomography, whereas the T/N ratio of FBPA is greater than 2.5. Additionally, in serving as a BNCT therapeutic agent, the boron concentration of FBY accumulated in gliomas remains uncertain. The solubility of 3-BPA is better than that of BPA, as evidenced by the cerebral dose of 3.4%ID/g vs. 2.2%ID/g, respectively. While the extraction route of d-BPA differs from that of BPA, an impressive T/N ratio of 6.9 vs. 1.5 is noted. [18F]FBPA, the most common clinical boron agent, facilitates the application of BPA in clinical BNCT. In addition to [18F]FBY, [18F] trifluoroborated nucleoside analog obtained through 1,3-dipolar cycloaddition shows marked tumoral uptake of 1.5%ID/g. Other examples using electrophilic and nucleophilic fluorination on the boron compounds are also reviewed, including diboronopinacolone phenylalanine and nonsteroidal anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

In this concise practitioner protocol, the radiochemical synthesis of 2′‐deoxy‐2′‐[18F]fluoro‐9‐β‐d‐arabinofuranosylguanine ([18F]FAraG) suitable for human positron emission tomography (PET) studies is described and the results from validation productions are presented. The high specific activity (sometimes referred to as molar activity) radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements established by the U.S. Food and Drug Administration. [ABSTRACT FROM AUTHOR]

Background: The somatostatin receptors 1–5 are overexpressed on neuroendocrine neoplasms and, as such, represent a favorable target for molecular imaging. This study investigates the potential of [18F]AlF-NOTA-[1-Nal3]-Octreotide and compares it in vivo to DOTA- and NOTA-[1-Nal3]-Octreotide radiolabeled with gallium-68. Methods: DOTA- and NOTA-NOC were radiolabeled with gallium-68 and NOTA-NOC with [18F]AlF. Biodistributions of the three radioligands were evaluated in AR42J xenografted mice at 1 h p.i and for [18F]AlF at 3 h p.i. Preclinical PET/CT was applied to confirm the general uptake pattern. Results: Gallium-68 was incorporated into DOTA- and NOTA-NOC in yields and radiochemical purities greater than 96.5%. NOTA-NOC was radiolabeled with [18F]AlF in yields of 38 ± 8% and radiochemical purity above 99% after purification. The biodistribution in tumor-bearing mice showed a high uptake in tumors of 26.4 ± 10.8 %ID/g for [68Ga]Ga-DOTA-NOC and 25.7 ± 5.8 %ID/g for [68Ga]Ga-NOTA-NOC. Additionally, [18F]AlF-NOTA-NOC exhibited a tumor uptake of 37.3 ± 10.5 %ID/g for [18F]AlF-NOTA-NOC, which further increased to 42.1 ± 5.3 %ID/g at 3 h p.i. Conclusions: The high tumor uptake of all radioligands was observed. However, [18F]AlF-NOTA-NOC surpassed the other clinically well-established radiotracers in vivo, especially at 3 h p.i. The tumor-to-blood and -liver ratios increased significantly over three hours for [18F]AlF-NOTA-NOC, making it possible to detect liver metastases. Therefore, [18F]AlF demonstrates promise as a surrogate pseudo-radiometal to gallium-68. [ABSTRACT FROM AUTHOR]

Amplification pretargeting strategies have great potential in nuclear medicine to increase the tumoral radioactivity concentration compared to conventional pretargeting. In this work, the dendrimer polyamidoamine generation 4 (PAMAM G4) was conjugated to multiple copies of peptide nucleic acid (PNA) as a signal amplification platform, which could combine with the antibody of CC49-cPNA and the tracer of 18F labeled complementary peptide nucleic acid (18F-cPNA) in biodistribution experiments to determine the signal amplification effect in vivo. The mice in the Amplification Group exhibited expected tumoral uptake (3.21 ± 0.77%ID/g), more than double that in the Pretargeting Group (1.21 ± 0.03%ID/g). Therefore, this work confirmed the signal amplification effect of dendrimer-PNA in vivo. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [18F]Favipiravir in naive mice, transgenic mice models of Alzheimer’s disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [18F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer’s disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [18F]Favipiravir in vivo. The [18F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET.

Abstract Background Prostate Membrane Specific Antigen (PSMA) positron emission tomography (PET) and multiparametric MRI (mpMRI) have shown high accuracy in identifying recurrent lesions after definitive treatment in prostate cancer (PCa). In this study, we aimed to outline patterns of failure in a group of post-prostatectomy patients who received adjuvant or salvage radiation therapy (PORT) and subsequently experienced biochemical recurrence, using 18F-PSMA PET/CT and mpMRI. Methods PCa patients with biochemical failure post-prostatectomy, and no evident site of recurrence on conventional imaging, were enrolled on two prospective trials of first and second generation 18F-PSMA PET agents (18F-DCFBC and 18F-DCFPyL) in combination with MRI between October 2014 and December 2018. The primary aim of our study is to characterize these lesions with respect to their location relative to previous PORT field and received dose. Results A total of 34 participants underwent 18F-PSMA PET imaging for biochemical recurrence after radical prostatectomy and PORT, with 32/34 found to have 18F-PSMA avid lesions. On 18F-PSMA, 17/32 patients (53.1%) had metastatic disease, 8/32 (25.0%) patients had locoregional recurrences, and 7/32 (21.9%) had local failure in the prostate fossa. On further exploration, we noted 6/7 (86%) of prostate fossa recurrences were in-field and were encompassed by 100% isodose lines, receiving 64.8–72 Gy. One patient had marginal failure encompassed by the 49 Gy isodose. Conclusions 18F-PSMA PET imaging demonstrates promise in identifying occult PCa recurrence after PORT. Although distant recurrence was the predominant pattern of failure, in-field recurrence was noted in approximately 1/5th of patients. This should be considered in tailoring radiotherapy practice after prostatectomy. Trial registration www.clinicaltrials.gov , NCT02190279 and NCT03181867. Registered July 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02190279 and June 8 2017, https://clinicaltrials.gov/ct2/show/NCT03181867 .

Abstract Introduction The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.

PurposeThe aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.MethodsSeveral conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.ResultsQuantitative labeling yields could be achieved with >97 % radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p

Amplification pretargeting has the potential to increase the tracer's accumulation in the tumor. This study aimed to develop a three‐step amplification pretargeting strategy in nuclear medicine with a polymer conjugated with multiple copies of peptide nuclear acid (PNA). In this study, the tracer 18F‐labeled complementary PNA (18F‐cPNA) was prepared by click‐chemistry with high radiochemical purity (>99%) and great stability in vitro. The PAMMA dendrimer generation 4 (G4) was conjugated with multiple copies of PNAs. The average number of PNA groups in the G4‐PNA conjugate was determined by matrix‐assisted laser desorption ionization‐time of flight mass spectrometry (MALDI‐TOF MS) and the accessibility to the 18F‐cPNA was identified by size‐exclusion high‐performance liquid chromatography (SE‐HPLC). There were approximately 11.7 of 64 carboxyl groups modified with PNAs, of which more than 99% were accessible to 18F‐cPNA. 18F‐cPNA was added to a mixture of CC49‐cPNA and G4‐PNA, and the complex exhibited a single peak on high‐performance liquid chromatography (HPLC) as evidence of complete hybridization between 18F‐cPNA and CC49‐cPNA/G4‐PNA. The LS174T tumor cells were incubated with CC49‐cPNA followed by G4‐PNA as an amplification platform before 18F‐cPNA was added to hybridize with CC49‐cPNA/G4‐PNA. Compared with conventional pretargeting without G4‐PNA, the radioactivity signal was amplified about four times, which demonstrated that the dendrimer–PNA conjugate plays a crucial role in signal amplification. [ABSTRACT FROM AUTHOR]

Nine fluorine-containing vesicular acetylcholine transporter (VAChT) inhibitors were synthesized and screened as potential PET tracers for imaging the VAChT. Compound 18a was one of the most promising carbonyl-containing benzovesamicol analogs; the minus enantiomer, (-)-18a displayed high potency (VAChT Ki=0.59 ± 0.06 nM) and high selectivity for VAChT versus σ receptors (>10,000-fold). The radiosynthesis of (-)-[(18)F]18a was accomplished by a two-step procedure with 30-40% radiochemical yield. Preliminary biodistribution studies of (-)-[(18)F]18a in adult male Sprague-Dawley rats at 5, 30, 60 and 120 min post-injection (p.i.) were promising. The total brain uptake of (-)-[(18)F]18a was 0.684%ID/g at 5 min p.i. and by 120 min p.i. slowly washed out to 0.409 %ID/g; evaluation of regional brain uptake showed stable levels of ∼0.800 %ID/g from 5 to 120 min p.i in the VAChT-enriched striatal tissue of rats, indicating the tracer had crossed the blood brain barrier and was retained in the striatum. Subsequent microPET brain imaging studies of (-)-[(18)F]18a in nonhuman primates (NHPs) showed high striatal accumulation in the NHP brain; the standardized uptake value (SUV) for striatum reached a maximum value of 5.1 at 15 min p.i. The time-activity curve for the target striatal region displayed a slow and gradual decreasing trend 15 min after injection, while clearance of the radioactivity from the cerebellar reference region was much more rapid. Pretreatment of NHPs with 0.25mg/kg of the VAChT inhibitor (-)-vesamicol resulted in a ∼90% decrease of striatal uptake compared to baseline studies. HPLC metabolite analysis of NHP plasma revealed that (-)-[(18)F]18a had a good in vivo stability. Together, these preliminary results suggest (-)-[(18)F]18a is a promising PET tracer candidate for imaging VAChT in the brain of living subjects.

Background: The somatostatin receptors 1–5 are overexpressed on neuroendocrine neoplasms and, as such, represent a favorable target for molecular imaging. This study investigates the potential of [18F]AlF-NOTA-[1-Nal3]-Octreotide and compares it in vivo to DOTA- and NOTA-[1-Nal3]-Octreotide radiolabeled with gallium-68. Methods: DOTA- and NOTA-NOC were radiolabeled with gallium-68 and NOTA-NOC with [18F]AlF. Biodistributions of the three radioligands were evaluated in AR42J xenografted mice at 1 h p.i and for [18F]AlF at 3 h p.i. Preclinical PET/CT was applied to confirm the general uptake pattern. Results: Gallium-68 was incorporated into DOTA- and NOTA-NOC in yields and radiochemical purities greater than 96.5%. NOTA-NOC was radiolabeled with [18F]AlF in yields of 38 ± 8% and radiochemical purity above 99% after purification. The biodistribution in tumor-bearing mice showed a high uptake in tumors of 26.4 ± 10.8 %ID/g for [68Ga]Ga-DOTA-NOC and 25.7 ± 5.8 %ID/g for [68Ga]Ga-NOTA-NOC. Additionally, [18F]AlF-NOTA-NOC exhibited a tumor uptake of 37.3 ± 10.5 %ID/g for [18F]AlF-NOTA-NOC, which further increased to 42.1 ± 5.3 %ID/g at 3 h p.i. Conclusions: The high tumor uptake of all radioligands was observed. However, [18F]AlF-NOTA-NOC surpassed the other clinically well-established radiotracers in vivo, especially at 3 h p.i. The tumor-to-blood and -liver ratios increased significantly over three hours for [18F]AlF-NOTA-NOC, making it possible to detect liver metastases. Therefore, [18F]AlF demonstrates promise as a surrogate pseudo-radiometal to gallium-68.

The goal of this work was to develop a reliable method to produce the well-validated microglial activation PET tracer, [18F]DPA-714, routinely for clinical and preclinical research using an IBA Synthera®. Optimization of literature methods included reduced precursor mass and use of TBA HCO 3 as the phase transfer agent in place of Kryptofix® 222 in a 65-min synthesis with an average activity yield of 24.6 ± 3.8% (n = 5). Successful quality control testing and process validation results are reported. • An IND-approved method for production of [18F]DPA-714 on an IBA Synthera® is reported. • Reduction of precursor mass and replacement of Kryptofix® 222 as phase transfer agent support production of tracer in reliable quantities for clinical research. • Justification of 5% injected ethanol in pediatric PET tracer preparations was outlined. [ABSTRACT FROM AUTHOR]

Recently, a novel radiohybrid tracer [18F]Lu-LuFL targeting the fibroblast activation protein (FAP) has been developed for PET imaging of solid tumors. This tracer has shown promising results, prompting us to conduct a first-in-human study to evaluate its efficacy for PET imaging of FAP in human body. In order to facilitate the routine production and clinical application of [18F]Lu-LuFL, a straightforward and efficient automated synthesis is described. The optimum labeling parameters were determined at laboratory scale, and subsequently incorporated into an automated production process. Further studies have demonstrated that clinical doses of [18F]Lu-LuFL can be prepared within 19 min, with excellent radio chemical purity (>99%) and activity yield (23.58% ± 2.20%, non-decay corrected), coupled with solid phase extraction (SPE) purification method. All the quality control results satisfy the required criteria for release. In conclusion, we have successfully synthesized [18F]Lu-LuFL with sufficient radioactivity and superior quality, thereby establishing its potential for further clinical application. • [18F]Lu-LuFL can be produced with an activity yield of 23.58% ± 2.20% within 19 min at r.t. in ALLINONE synthesis module. • This preparation of [18F]Lu-LuFL utilizing SiFA 18F–19F isotope exchange is very robust and highly reliable. • [18F]Lu-LuFL produced by ALLINONE synthesis module meets our quality control and release criteria. • [18F]Lu-LuFL showed promising tumor accumulation and favorable pharmacokinetics. [ABSTRACT FROM AUTHOR]

Background: Prostate Membrane Specific Antigen (PSMA) positron emission tomography (PET) and multiparametric MRI (mpMRI) have shown high accuracy in identifying recurrent lesions after definitive treatment in prostate cancer (PCa). In this study, we aimed to outline patterns of failure in a group of post-prostatectomy patients who received adjuvant or salvage radiation therapy (PORT) and subsequently experienced biochemical recurrence, using 18F-PSMA PET/CT and mpMRI.Methods: PCa patients with biochemical failure post-prostatectomy, and no evident site of recurrence on conventional imaging, were enrolled on two prospective trials of first and second generation 18F-PSMA PET agents (18F-DCFBC and 18F-DCFPyL) in combination with MRI between October 2014 and December 2018. The primary aim of our study is to characterize these lesions with respect to their location relative to previous PORT field and received dose.Results: A total of 34 participants underwent 18F-PSMA PET imaging for biochemical recurrence after radical prostatectomy and PORT, with 32/34 found to have 18F-PSMA avid lesions. On 18F-PSMA, 17/32 patients (53.1%) had metastatic disease, 8/32 (25.0%) patients had locoregional recurrences, and 7/32 (21.9%) had local failure in the prostate fossa. On further exploration, we noted 6/7 (86%) of prostate fossa recurrences were in-field and were encompassed by 100% isodose lines, receiving 64.8-72 Gy. One patient had marginal failure encompassed by the 49 Gy isodose.Conclusions: 18F-PSMA PET imaging demonstrates promise in identifying occult PCa recurrence after PORT. Although distant recurrence was the predominant pattern of failure, in-field recurrence was noted in approximately 1/5th of patients. This should be considered in tailoring radiotherapy practice after prostatectomy. Trial registration www.clinicaltrials.gov , NCT02190279 and NCT03181867. Registered July 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02190279 and June 8 2017, https://clinicaltrials.gov/ct2/show/NCT03181867 . [ABSTRACT FROM AUTHOR]

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods: [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results: The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion: This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts. [ABSTRACT FROM AUTHOR]

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[Display omitted] The ghrelin receptor (GHSR) is known to regulate various physiological processes including appetite, food intake, and growth hormone release. Its expression is mainly observed in the brain, pancreas, stomach, and intestine. However, the functions of the receptor have not been fully elucidated. GHSR imaging with positron emission tomography (PET) is expected to further understanding of the functions and pathologies of the receptor. In this study, we newly designed and synthesized diaminopyrimidine derivatives ([18F]BPP-1 and [18F]BPP-2) and evaluated their utility as novel PET probes targeting GHSR. In in vitro competitive binding assays, the binding affinity of BPP-2 for GHSR (K i = 274 nM) was comparable to that of the diaminopyimidine lead compound Abb8a (K i = 109 nM). In a biodistribution study using normal mice, [18F]BPP-2 displayed low uptake in the brain and moderate uptake in the pancreas, but high radioactivity accumulation in bone was observed due to its defluorination in vivo. Taken together, although further improvement of the pharmacokinetics is needed, the diaminopyrimidine scaffold has potential for the development of useful GHSR-targeting PET probes. [ABSTRACT FROM AUTHOR]

Nicotine alpha(4)beta(2) receptor subtypes are implicated in the study of Alzheimer's disease, schizophrenia, substance abuse, lung cancer, and other disorders. We report the development and evaluation of a putative antagonist, 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (nifrolidine) as a PET agent for nicotine alpha(4)beta(2) receptors. Methods: In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with I-125-iodoepibatidine or I-125-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. F-18 radiolabeling was performed by reacting the tosylate precursor with F-18-fluoride followed by cleprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-F-18-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (F-18-nifrolidine) were read on a phosphor imager. Rats were injected with F-18-nifrolidine (3.7 MBq each), and brain regions were counted at various times (2-120 min). Blocking studies were performed by subcutaneous injection of nicotine (10 mg/kg). A PET study of F-18-nifrolidine (approximately 148 MBq) was performed on an anesthetized rhesus monkey using a high-resolution scanner. Results: In vitro binding affinity of nifrolidine exhibited an inhibition constant of 2.89 nmol/L for the alpha(4)beta(2) sites. Radiosynthesis and high-performance liquid chromatography purifications yielded the product in approximately 20%-40% decay-corrected radiochemical yield to provide 18F-nifrolidine specific activities of approximately 111-185 GBq/mumol. In vitro autoradiography in rat brain slices revealed selective binding of F-18-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain alpha(4)beta(2) sites. This specific binding was completely abolished by 300 mumol/L nicotine. Ex vivo rat brain distribution studies indicated selective binding in the thalamus with a maximal thalamus-to-cerebellum ratio of approximately 3. The PET study revealed selective maximal uptake (0.01 % injected dose/mL) in regions of the thalamus (anteroventral and anteromedial mus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex. Conclusion: Binding of F-18-nifrolidine to alpha(4)beta(2) receptor-rich regions in rats and monkeys indicates promise as a PET agent. Additionally, the thalamus-to-cerebellum ratio approached a plateau of 1.7 in 120 min, indicating relatively faster kinetics compared with previously reported imaging agents.

Abstract Background The P2X7 receptor has been shown to play a fundamental role in the initiation and sustenance of the inflammatory cascade. The development of a novel fluorine-18 PET tracer superior and with a longer half-life to those currently available is a promising step towards harnessing the therapeutic and diagnostic potential offered by this target. Inspired by the known antagonist A-804598, the present study outlines the design via molecular docking, synthesis and biological evaluation of the novel P2X7 tracer [18F]EFB. The tracer was radiolabelled via a three-step procedure, in vitro binding assessed in P2X7-transfected HEK293 and in B16 cells by calcium influx assays and an initial preclinical evaluation was performed in a lipopolysaccharide (LPS)-injected rat model of neuroinflammation. Results The novel tracer [18F]EFB was synthesised in 210 min in 3–5% decay-corrected radiochemical yield (DC RCY), >99% radiochemical purity (RCP) and >300 GBq/μmol and fully characterised. Functional assays showed that the compound binds with nM K i to human, rat and mouse P2X7 receptors. In vivo, [18F]EFB displayed a desirable distribution profile, and while it showed low blood–brain barrier penetration, brain uptake was quantifiable and displayed significantly higher mean longitudinal uptake in inflamed versus control rat CNS regions. Conclusions [18F]EFB demonstrates strong in vitro affinity to human and rodent P2X7 and limited yet quantifiable BBB penetration. Considering the initial promising in vivo data in an LPS rat model with elevated P2X7 expression, this work constitutes an important step in the development of a radiotracer useful for the diagnosis and monitoring of clinical disorders with associated neuroinflammatory processes.

One of the key strategies for radiochemical research facilities is the automation of synthesis processes. Unnecessary manual operations increase the radiation exposure of personnel, while simultaneously threatening the reliability of syntheses. We have previously reported an affordable open-source system comprising 3D-printed continuous flow reactors, a custom syringe pump, and a pressure regulator that can be used to perform radiofluorinations. In this paper, we address additional essential processes that are needed for radiotracer development and synthesis, with the aim of making laboratory work safer and research more efficient. We have designed and evaluated a fully automated system for rapidly and effectively processing and drying aqueous [ 18 F]fluoride that can be directly connected to the cyclotron. This process relies on triflyl fluoride gas generation and allows nucleophilic [ 18 F]fluoride to be prepared safely in a hotcell within 10 min and an activity recovery of 91.7 ± 1.6% (n = 5). Owing to the need for convenient radiofluorinated prosthetic ligands, we have adapted our continuous flow system to produce [ 18 F]fluoroethyl tosylate (FEOTs) and [ 18 F]fluoroethyl triflate (FEOTf), prosthetic groups that are widely used for late-stage fluoroethylation of PET tracers. The processes as well as the radiolabeling of different groups are compared and comprehensively discussed. Having a method providing [ 18 F]fluoroethyl tosylate (FEOTs) as well as [ 18 F]fluoroethyl triflate (FEOTf) quickly and highly efficiently is beneficial for radiochemical research., (© 2023 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

Purpose: Synaptic vesicle protein 2A (SV2A) serves as a biomarker of synaptic density and positron emission tomography (PET) imaging of SV2A could provide a tool to assess progression of neurodegenerative diseases. Two tracers have primarily been reported and characterized in vivo: [11C]UCB-J and [18F]UCB-H. In early human studies, [11C]UCB-J showed promising results, while its F-18-labeled analogue [18F]UCB-H showed suboptimal specific signal in comparison to [11C]UCB-J. Considering the limited use of [11C]UCB-J to facilities with a cyclotron, having a F-18 variant would facilitate large, multicenter imaging trials. We have screened several F-18 derivatives of UCB-J in non-human primates and identified a promising F-18 PET candidate, [18F]MNI-1126, with additional investigations of the racemate [18F]MNI-1038, affording a signal comparable to [11C]UCB-J.Procedures: F-18 derivatives of UCB-J and UCB-H were synthesized and administered to non-human primates for microPET imaging. Following screenings, [18F]MNI-1038 (racemate) and [18F]MNI-1126 (R-enantiomer) were identified with the highest signal and favorable kinetics and were selected for further imaging. Kinetic modeling with one- and two-tissue compartmental models, and linear methods were applied to PET data using metabolite-corrected arterial input function. Pre-block scans with levetiracetam (LEV, 10, 30 mg/kg, iv) were performed to determine the tracers' in vivo specificity for SV2A. Two whole-body PET studies were performed with [18F]MNI-1038 in one male and one female rhesus, and radiation absorbed dose estimates and effective dose (ED, ICRP-103) were estimated with OLINDA/EXM 2.0.Results: All compounds screened displayed very good brain penetration, with a plasma-free fraction of ~ 40 %. [18F]MNI-1126 and [18F]MNI-1038 showed uptake and distribution the most consistent with UCB-J, while the other derivatives showed suboptimal results, with similar or lower uptake than [18F]UCB-H. VT of [18F]MNI-1126 and [18F]MNI-1038 was high in all gray matter regions (within animal averages ~ 30 ml/cm3) and highly correlated with [11C]UCB-J (r > 0.99). Pre-blocking of [18F]MNI-1126 or [18F]MNI-1038 with LEV showed robust occupancy across all gray matter regions, similar to that reported with [11C]UCB-J (~ 85 % at 30 mg/kg, ~ 65 % at 10 mg/kg). Using the centrum semiovale as a reference region, BPND of [18F]MNI-1126 reached values of up to ~ 30 to 40 % higher than those reported for [11C]UCB-J. From whole-body imaging average ED of [18F]MNI-1038 was estimated to be 22.3 μSv/MBq, with tracer being eliminated via both urinary and hepatobiliary pathways.Conclusions: We have identified a F-18-labeled tracer ([18F]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [11C]UCB-J in non-human primates, which makes [18F]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials. [ABSTRACT FROM AUTHOR]

The imaging of reactive oxygen species (ROS) at the molecular level with high sensitivity and specificity by positron emission tomography (PET) could be of enormous interest to increase our knowledge about ROS activity and signalling, especially in tumours. The aim of this research was to optimise the click chemistry‐based radiosynthesis of an 18F‐labelled aminoferrocene glycoconjugate that was derived from an N‐alkylaminoferrocene lead structure known to have anticancer activity in vitro. Applying the solvent system phosphate buffer/THF (12/5), Cu(OAc)2 and sodium ascorbate as reducing agent at 60°C, the alkyne 1 reacted with the 18F‐labelled glycosyl azide [18F]2 in the presence of carrier 3 (47μM) to obtain carrier‐added [18F]4 in a radiochemical yield of 85%. Interestingly, the addition of carrier was essential for sufficient radiochemical yield, because it suppressed the oxidation of no‐carrier‐added (n.c.a.) [18F]4. Future work will include the formulation of c.a. [18F]4 for studying its biodistribution in tumour‐bearing mice. In vivo imaging of reactive oxygen species (ROS) represents a promising strategy for diagnosis and therapy of several types of cancer. In this study, the 18F‐fluoroglycosylation of an aminoferrocene derivative as a potential positron emission tomography (PET) tracer with ROS‐dependent cell uptake mechanism was optimised, providing a radiochemical yield of 85%. Further studies on its biodistribution and in vivo suitability as a ROS‐specific PET tracer are ongoing. [ABSTRACT FROM AUTHOR]

To the best of our knowledge, imaging of accidental exposure to radioactive fluorine-18 (F-18) due to liquid spill has not been described earlier in the scientific literature. The short half-life of F-18 (t½=110 min), current radiation safety requirements, and Good Manufacturing Practice (GMP) regulations on radiopharmaceuticals have restrained the occurrence of these incidents. The possibility of investigating this type of incidents by gamma and positron imaging is also quite limited. Additionally, a quick and precise analysis of radiochemical contamination is cumbersome and sometimes challenging if the spills of radioactive materials are low in activity. Herein, we report a case of accidental F-18 contamination in a service person during a routine cyclotron maintenance procedure. During target replacement, liquid F-18 was spilled on the person responsible for the maintenance. The activities of spills were immediately measured using contamination detectors, and the photon spectrum of contaminated clothes was assessed through gamma spectroscopy. Despite protective clothing, some skin areas were contaminated, which were then thoroughly washed. Later on, these areas were imaged, using positron emission tomography (PET), and a gamma camera (including spectroscopy). Two contaminated skin areas were located on the hand (9.7 and 14.7 cm2, respectively), which showed very low activities (19.0 and 22.8 kBq respectively at the time of incident). Based on the photon spectra, F-18 was confirmed as the main present radionuclide. PET imaging demonstrated the shape of these contaminated hot spots. However, the measured activities were very low due to the use of protective clothing. With prompt action and use of proper equipments at the time of incident, minimal radionuclide activities and their locations could be thoroughly analyzed. The cumulative skin doses of the contaminated regions were calculated at 1.52 and 2.00 mSv, respectively. In the follow-up, no skin changes were observed in the contaminated areas.

Purpose: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues.Procedures: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (Kcat/Km 716.5 ± 72.8, 615.4 ± 50.5, 269.5 ± 52.1/s mol, respectively). Radiosynthesis of 12- [18F]fluorododecanoic aminohexanoicanilide (12-[18F]DDAHA) was achieved by nucleophilic radiofluorination of 12-iododecanoic-AHA precursor.Results: A significantly higher accumulation of 12-[18F]DDAHA was observed in MCF-7 and MDA-MB-435 cells in vitro as compared to U87, MiaPaCa, and MCF10A, which was consistent with levels of SIRT2 expression. Initial in vivo studies using 12-[18F]DDAHA conducted in a 9L glioma-bearing rats were discouraging, due to rapid defluorination of this radiotracer upon intravenous administration, as evidenced by significant accumulation of F-18 radioactivity in the skull and other bones, which confounded the interpretation of images of radiotracer accumulation within the tumor and other regions of the brain.Conclusions: The next generation of SIRT2-specific radiotracers resistant to systemic defluorination should be developed using alternative sites of radiofluorination on the aliphatic chain of DDAHA. A SIRT2-selective radiotracer may provide information about SIRT2 expression and activity in tumors and normal organs and tissues, which may help to better understand the roles of SIRT2 in different diseases. [ABSTRACT FROM AUTHOR]

Accumulation of triphenylphosphonium (TPP) is normally observed in the mitochondria from the extracellular spaces due to the high difference in plasma membrane potential of the mitochondria. In the cancer cells, the mitochondrial membrane potential gap is higher as compared to that of normal cells resulting in elevated uptake of TPP. Silica nanoparticles (SNPs) being widely developed and used for biomedical applications, in this study, we tried to modify the surface of SNPs with varying amounts of TPP to verify their possible application as a positron emission tomography (PET) agent. The studies confirmed that the high level of TPP loading on the surface of SNPs possess higher positive charge (+ 31.5 mV). Owing to this behavior of plasma membrane potential of cancerous cells the uptake of positively charged SNPs was much higher in tumor cells than that of normal cells which was confirmed by PET imaging. [ABSTRACT FROM AUTHOR]

4‐Aminopyridine is a clinically approved drug to improve motor symptoms in multiple sclerosis. A fluorine‐18‐labeled derivative of this drug, 3‐[18F]fluoro‐4‐aminopyridine, is currently under investigation for positron emission tomography (PET) imaging of demyelination. Herein, the Yamada‐Curtius reaction has been successfully applied for the preparation of this PET radioligand with a better radiochemical yield and improved specific activity. The overall radiochemical yield was 5 to 15% (n = 12, uncorrected) with a specific activity of 37 to 148 GBq/μmol (end of synthesis) in a 90 minute synthesis time. It is expected that this 1 pot Yamada‐Curtius reaction can be used to prepare similar fluorine‐18‐labeled amino substituted heterocycles. [ABSTRACT FROM AUTHOR]

Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi‐step procedures, especially for fluorine‐18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2‐[18F]fluoropropionate labeled RGD‐peptides through use of the iPHASE Flexlab as an effective dual‐stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD‐peptides, [18F]FP‐GalactoRGD and [18F]FP‐c(RGDy(SO3)K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD‐peptides, [18F]F‐PRGD2 and [18F]FP‐E(RGDy(SO3)K)2, was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride. [ABSTRACT FROM AUTHOR]

Ra-223 has recently been introduced in alpha-targeting radionuclide therapy. According to the decay scheme of Ra-223, beta particles with higher energy than the Cerenkov-light threshold are emitted. In addition, there are reports that the alpha particles themselves emit luminescence in water and air. However, measured optical imaging results from Ra-223 have not yet been reported. Therefore, we conducted optical imaging of an Ra-223 solution and compared it with that of an F-18 solution. Ra-223 and F-18 solutions contained in transparent glass vials were imaged using a high-sensitivity CCD camera. We could obtain an image of the Ra-223 solution with radioactivity of 0.72 MBq in an acquisition time of less than 10 s. At the same level of radioactivity, the intensity of the optical signal in the solution part of the vial of Ra-223 was 21 times higher than that of F-18. Furthermore, in the air part of the vials, Ra-223 had higher luminescence than that of F-18. The light spectra for Ra-223 and F-18 solutions were similar, but those in the vials' air parts were different. The optical signals in the solution part of both Ra-223 and F-18 are attributed to Cerenkov light, while that in the air part of Ra-223 is attributed to the scintillation of N 2 gas in air. No obvious luminescence of water by the alpha particles was observed. We concluded that optical imaging of the Ra-223 solution was possible, and this solution's light intensity was much higher than that of the F-18 solution and thus easier to detect. Therefore, Ra-223 is a promising radionuclide for optical imaging in distribution measurements. [ABSTRACT FROM AUTHOR]

Purpose: Prostate-specific membrane antigen (PSMA) is an important biomarker expressed in the majority of prostate cancers. The favorable positron emission tomography (PET) imaging profile of the PSMA imaging agent 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentane-dioic acid [18F]DCFPyL in preclinical prostate cancer models and in prostate cancer patients stimulated the development and validation of other fluorine-containing PSMA inhibitors to further enhance pharmacokinetics and simplify production methods. Here, we describe the synthesis and radiopharmacological evaluation of various F-18-labeled PSMA inhibitors which were prepared through different prosthetic group chemistry strategies.Procedures: Prosthetic groups N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), 4-[18F]fluorobenzaldehyde, and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) were used for bioconjugation reactions to PSMA-binding lysine-urea-glutamate scaffold via acylation and oxime formation. All fluorine-containing PSMA inhibitors were tested for their PSMA inhibitory potency in an in vitro competitive binding assay in comparison to an established reference compound [125I]TAAG-PSMA. Tumor uptake and clearance profiles of three F-18-labeled PSMA inhibitors ([18F]4, [18F]7, and [18F]8) were studied with dynamic PET imaging using LNCaP tumor-bearing mice.Results: F-18-labeled PSMA inhibitors were synthesized in 32-69 % radiochemical yields using (1) acylation reaction at the primary amino group of the lysine residue with [18F]SFB and (2) oxime formation with 4-[18F]fluorobenzaldehyde and [18F]FDG using the respective aminooxy-functionalized lysine residue. Compound 7 displayed an IC50 value of 6 nM reflecting very high affinity for PSMA. Compounds 4 and 8 showed IC50 values of 13 and 62 nM, respectively. The IC50 value of reference compound DCFPyL was 13 nM. Dynamic PET imaging revealed the following SUV60min for radiotracer uptake in PSMA(+) LNCaP tumors: 0.98 ([18F]DCFPyL), 2.11 ([18F]7), 0.40 ([18F]4), and 0.19 ([18F]8).Conclusion: The observed tumor uptake and clearance profiles demonstrate the importance of the selected prosthetic group on the pharmacokinetic profile of analyzed PSMA-targeting radiotracers. Radiotracer [18F]7 displayed the highest uptake and retention in LNCaP tumors, which exceeded uptake values of reference compound [18F]DCFPyL by more than 100 %. Despite the higher kidney and liver uptake and retention of compound [18F]7, the simple radiosynthesis and the exceptionally high tumor uptake (SUV60min 2.11) and retention make radiotracer [18F]7 an interesting alternative to radiotracer [18F]DCFPyL for PET imaging of PSMA in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The P2X7 receptor has been shown to play a fundamental role in the initiation and sustenance of the inflammatory cascade. The development of a novel fluorine-18 PET tracer superior and with a longer half-life to those currently available is a promising step towards harnessing the therapeutic and diagnostic potential offered by this target. Inspired by the known antagonist A-804598, the present study outlines the design via molecular docking, synthesis and biological evaluation of the novel P2X7 tracer [F]EFB. The tracer was radiolabelled via a three-step procedure, in vitro binding assessed in P2X7-transfected HEK293 and in B16 cells by calcium influx assays and an initial preclinical evaluation was performed in a lipopolysaccharide (LPS)-injected rat model of neuroinflammation. Results: The novel tracer [F]EFB was synthesised in 210 min in 3-5% decay-corrected radiochemical yield (DC RCY), >99% radiochemical purity (RCP) and >300 GBq/μmol and fully characterised. Functional assays showed that the compound binds with nM K to human, rat and mouse P2X7 receptors. In vivo, [F]EFB displayed a desirable distribution profile, and while it showed low blood-brain barrier penetration, brain uptake was quantifiable and displayed significantly higher mean longitudinal uptake in inflamed versus control rat CNS regions. Conclusions: [F]EFB demonstrates strong in vitro affinity to human and rodent P2X7 and limited yet quantifiable BBB penetration. Considering the initial promising in vivo data in an LPS rat model with elevated P2X7 expression, this work constitutes an important step in the development of a radiotracer useful for the diagnosis and monitoring of clinical disorders with associated neuroinflammatory processes. [ABSTRACT FROM AUTHOR]

Fluorine-18 labeling of biomolecules is mostly performed by an indirect labeling method using a prosthetic group. Fluorine-18 labeled 6-fluoronicotinic acid-2,3,5,6-tetrafluorophenyl ester is a useful prosthetic group to radiolabel a protein. Recently, we reported an improved preparation of this prosthetic group. To test the conjugation efficiency of the labeled ester prepared by this method, we have performed conjugation reactions with a peptide, a protein, and a small molecule. Prostate-specific membrane antigen targeting small molecule [18F]DCFPyL, αvβ3 integrin receptors targeting peptide [18F]c(RGDfK) and [18F]albumin were prepared in good radiochemical yields. The conjugation reactions were completed at 40°C to 50°C in 10 minutes. The overall radiochemical yield was 25% to 43% in 30 to 45 minutes. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([ 18 F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [ 18 F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [ 18 F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [ 18 F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [ 18 F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.