A practical, rapid, and highly regioselective Cu-catalyzed radiofluorination of (mesityl)(aryl)iodonium salts is described. This protocol utilizes 18FKF to access 18F-labeled electron-rich, ...-neutral, and -deficient aryl fluorides under a single set of mild conditions. This methodology is applied to the synthesis of protected versions of two important radiotracers: 4-18Ffluorophenylalanine and 6-18FfluoroDOPA.
Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). ...However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using
Ccarfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids.
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy ...disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized 18Flansoprazole, 11CN-methyl lansoprazole, and 18FN-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that 18FN-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
Background
In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be ...conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be
intended
for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing.
Results
The University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees.
Conclusions
The data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.
A novel one-pot method for preparing 18Ffluoromethylcholine (18FFCH) via in situ generation of 18Ffluoromethyl tosylate (18FFCH2OTs), and subsequent 18Ffluoromethylation of dimethylaminoethanol ...(DMAE), has been developed.
18FFCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-18 synthesis module. Initially ditosylmethane was fluorinated to generate 18FFCH2OTs. DMAE was then added and the reaction was heated at 120°C for 10min to generate 18FFCH. After this time, reaction solvent was evaporated, and the crude reaction mixture was purified by solid-phase extraction using C18-Plus and CM-Light Sep-Pak cartridges to provide 18FFCH formulated in USP saline. The formulated product was passed through a 0.22µm filter into a sterile dose vial, and submitted for quality control testing. Total synthesis time was 1.25h from end-of-bombardment.
Typical non-decay-corrected yields of 18FFCH prepared using this method were 91mCi (7% non-decay corrected based upon ∼1.3Ci 18Ffluoride), and doses passed all other quality control (QC) tests.
A one-pot liquid-phase synthesis of 18FFCH has been developed. Doses contain extremely low levels of residual DMAE (31.6µg/10mL dose or ∼3ppm) and passed all other requisite QC testing, confirming their suitability for use in clinical imaging studies.
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•A novel fully automated synthesis of 18Ffluoromethylcholine has been developed•Typical non-decay-corrected yields were 91mCi (7% non-decay corrected, n=3)•QC testing confirmed suitability for clinical use (RCP >99%; SA 16,147Ci/mmol)•Doses contain amongst the lowest residual DMAE ever reported
Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging. Historically they have been labeled with SPECT radionuclides. A PET blood pool imaging agent is ...highly desirable as it would improve clinical applications with better image quality and resolution, higher sensitivity, and dynamic scanning capabilities. With the coming of age of modern 68Ge/68Ga generator systems, gallium-68 is now widely accessible. In this paper we describe an updated method for the preparation of 68Ga-labeled erythrocytes and their preliminary use in rodent blood pool imaging. A novel automated synthesis of 68Gaoxine using a 68Ga/68Ge generator and automated synthesis module is reported. 68GaOxine was synthesized in 50 ± 5% (n = 3) non-decay corrected radiochemical yield and >99% radiochemical purity. Rat and human erythrocytes were successfully labeled with the complex in 42% RCY, and the 68Ga-labeled erythrocytes have been shown to clearly image the blood pool in a healthy rat. Human erythrocytes labelled with 68Gaoxine were shown to be viable up to 2 hours post-labelling, and washout of the radiolabel was minimal up to 1 hour post-labelling. Further optimization of the labeling method to translate for use in human cardiac and oncologic blood pool PET imaging studies, is underway.
Purpose
To optimize the direct production of
68
Ga on a cyclotron, via the
68
Zn(p,n)
68
Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced
68
Ga, extraction ...of
68
GaGaCl
3
and subsequent
68
GaGa-PSMA-11 labeling using an automated synthesis module.
Methods
Irradiations of a 1.0 M solution of
68
ZnZn(NO
3
)
2
in dilute (0.2–0.3 M) HNO
3
were conducted using GE PETtrace cyclotrons and GE
68
Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of
67
Ga through the
68
Zn(p,2n)
67
Ga reaction without unduly compromising
68
Ga yields. We also evaluated the effects of varying beam times (50–75 min) and beam currents (27–40 μA). Crude
68
Ga production was measured. The extraction of
68
GaGaCl
3
was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted
68
GaGaCl
3
was used to label
68
GaGa-PSMA-11 that was intended for clinical use.
Results
The decay corrected yield of
68
Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of
68
ZnZn(NO
3
)
2
at 0.3 M HNO
3.
Target/chemistry performance was more consistent when compared with 0.2 M HNO
3
. Radionuclidic purity of
68
Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia (< 2% combined
66/67
Ga) for a practical clinical product shelf-life. The activity yield of
68
GaGaCl
3
was typically > 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for
68
GaGa-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced
68
GaGa-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA).
Conclusion
Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of
68
GaGa-PSMA-11 and is a viable alternative to traditional
68
Ge/
68
Ga generators.
Abstract Cathepsin K is a cysteine peptidase primarily located in osteoclasts, cells involved in normal growth and remodeling of bone but that are also responsible for bone loss in osteolytic ...diseases such as osteoporosis. In vivo imaging of cathepsin K may provide a method to assess changes in osteoclast numbers in such disease states. To that end, two high-affinity and selective cathepsin K inhibitors were radiolabeled with carbon-11. In vivo microPET imaging studies demonstrated uptake and prolonged retention of radioactivity in actively growing or remodeling bone regions (e.g., distal ulnar, carpal, distal and proximal humeral, distal femur, proximal tibia, tail vertebrae). Uptake into bone could be blocked by pre- or co-injection of unlabeled ligand, supporting a specific and saturable binding mechanism for radiotracer localization. These proof-of-concept studies indicate that radiolabeled cathepsin K inhibitors may have potential as in vivo imaging radiotracers for assessing changes of osteoclast numbers in osteolytic diseases.
Abstract Introduction Two 7-fluoroimidazobenzodiazepines (AH114726 and GEH120348), analogs of flumazenil, were labeled with fluorine-18 and evaluated as alternative radioligands for in vivo imaging ...of the GABAA /benzodiazepine receptor by comparing them to 11 Cflumazenil in rhesus monkey. Methods Radiotracers were prepared from the corresponding nitro-precursors in an automated synthesis module, and primate imaging studies were conducted on a Concorde MicroPET P4 scanner. The brain was imaged for 60 (12 × 5 min frames) or 90 min (18 × 5 min frames), and data was reconstructed using the 3D MAP algorithm. Specificity of 18 FAH114726 and 18 FGEH120348 was confirmed by displacement studies using unlabeled flumazenil. Results 18 FGEH120348 and 18 FAH114726 were obtained in 13–24% yields (end of synthesis) with high chemical (> 95%) and radiochemical (> 99%) purities, and high specific activities (2061 ± 985 Ci/mmol). The in vivo pharmacokinetics of 18 FAH114726 and 18 FGEH120348 were determined in a non-human primate and directly compared with 11 Cflumazenil. Both fluorine-18 radioligands showed time-dependent regional brain distributions that correlated with the distribution of 11 Cflumazenil and the known concentrations of GABAA /benzodiazepine receptors in the monkey brain. 18 FAH114726 exhibited maximal brain uptake and tissue time-radioactivity curves that were most similar to 11 Cflumazenil. In contrast, 18 FGEH120348 showed higher initial brain uptake but very different pharmacokinetics with continued accumulation of radioactivity into the cortical regions of high GABA/benzodiazepine receptor concentrations and very little clearance from the regions of low receptor densities. Rapid washout of both radiotracers occurred upon treatment with unlabeled flumazenil. Conclusion The ease of the radiochemical synthesis, together with in vivo brain pharmacokinetics most similar to 11 Cflumazenil, support that 18 FAH114726 is a suitable option for imaging the GABAA receptor.
Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging. Historically they have been labeled with SPECT radionuclides. A PET blood pool imaging agent is ...highly desirable as it would improve clinical applications with better image quality and resolution, higher sensitivity, and dynamic scanning capabilities. With the coming of age of modern
68
Ge/
68
Ga generator systems, gallium-68 is now widely accessible. In this paper we describe an updated method for the preparation of
68
Ga-labeled erythrocytes and their preliminary use in rodent blood pool imaging. A novel automated synthesis of
68
Gaoxine using a
68
Ga/
68
Ge generator and automated synthesis module is reported.
68
GaOxine was synthesized in 50 ± 5% (
n
= 3) non-decay corrected radiochemical yield and >99% radiochemical purity. Rat and human erythrocytes were successfully labeled with the complex in 42% RCY, and the
68
Ga-labeled erythrocytes have been shown to clearly image the blood pool in a healthy rat. Human erythrocytes labelled with
68
Gaoxine were shown to be viable up to 2 hours post-labelling, and washout of the radiolabel was minimal up to 1 hour post-labelling. Further optimization of the labeling method to translate for use in human cardiac and oncologic blood pool PET imaging studies, is underway.
Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging.
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