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Synthesis of 11C Labeled Lansoprazole: A Novel Radiopharmaceutical for the Alzheimer’s disease is a serious and common form of dementia, affecting nearly half of the population over 85 years of age (Source: Mayo Clinic). As of now, this disease has no cure and can only be definitively diagnosed by risky diagnostic procedures such as brain biopsy or upon post-mortem examination of the brain. The cause of Alzheimer’s disease is not completely understood and is often contributed to several compounding factors know as a neurodegenerative cascade. One theory is that abnormal aggregates of tau protein, called neurofibrillary tangles (NFT’s), build up in the brain, causing a disruption in neuronal functioning which leads to cognitive decline. The focus of this research is to develop a chemical radiolabeling technique to label lansoprazole, a drug that has shown a high affinity for tau tangles, with carbon-11. The resulting drug will be used to image tau tangles using positron emission tomography (PET). The products of the reactions are characterized with various methods including HPLC, TLC, and NMR. Future imaging studies with rodents will be used to determine if the biomarker developed is a realistic radioligand for PET imaging of tau. It is anticipated that these drugs will provide information about the density and mass of tau tangles that could one day be used to diagnose various tauopathies, select appropriate patients for the development of tau-based therapeutics, and monitor patient response to therapy. The results of radiopharmaceutical synthesis will be reported. Keywords PET, Alzheimer’s disease, Radiochemistry 1. Introduction 1.1 Introduction To Dementia Alzheimer’s disease and other neurodegenerative tauopathies such as fronto-temporal dementia and Parkinson’s disease are characterized by intracellular accumulations of tau proteins as neurofibrillary tangles (NFTs) in the brain1. Many of these diseases produce similar clinical symptoms, making it difficult for doctors to distinguish between overlapping tauopathy disease entities and treat each appropriately. The overall goal of this research is to improve diagnostic confidence across the entire spectrum of tauopathies by developing radiopharmaceuticals that enable quantification of tau burden in living human subjects using positron emission tomography (PET) imaging. A tau specific radiopharmaceutical would lead to earlier and more definitive diagnosis of these types of diseases and provide a better way to monitor patient response to therapy. When selecting a suitable scaffold to develop into a tau specific radiopharmaceutical, we were inspired by a paper by Rojo and colleagues that described research suggesting that the drug lansoprazole has a high binding affinity for tau proteins2. This report describes our progress in preparing a radiolabeled analog of lansoprazole suitable for PET imaging of tau NFTs. 1.2 Introduction To Positron Emission Tomography Positron emission tomography (PET) is a form of functional molecular imaging used to elucidate biological processes. It is most widely known for its ability to detect certain forms of cancer, but new uses for the technology are constantly being discovered. PET imaging relies on radioactive drugs known as radiopharmaceuticals. These drugs are labeled with positron emitting atoms such as carbon-11 and fluorine-18. When injected into the body, radiopharmaceuticals interact in different ways with the body while emitting high energy gamma radiation. This radiation travels through body tissues and is detected by the PET scanner. A computer then interprets the information from the PET scanner and constructs a three dimensional image of the inside of the body. Often times, PET is paired with CT scanning to better visualize structures of the body. PET has applications in cardiology, 3 oncology,4 and neurology5. This research focuses on developing a new radiopharmaceutical called [11C]N-Methyl Lansoprazole, a drug designed to enter the brain and bind specifically to tau NFTs, enabling the quantification of the tau burden in AD patients. If such a drug is developed, it could become an important tool in future diagnostic medicine and treatment development. 2. Experimental 2.1 Synthesis Of Methylated Lansoprazole Reference Standard All chemical reagents were purchased commercially from Sigma-Aldrich and used without any further purification. A methylated lansoprazole reference standard was first synthesized for classification purposes (see figure 1). This reaction was performed as follows: 99.7 mg of lansoprazole was added to 5 mL of water. An 8 molar equivilient of potassium hydroxide (5M) was added to the flask to ionize and dissolve the lansoprazole starting material. The solution was then sonicated until all the lansoprazole had dissolved. Iodomethane was added to the reaction flask and the solution was sonicated until the solution turned white and cloudy. The solution was heated in a water bath at 60°C for 10 mins while stirring. The solution was cooled in ice water for 10 mins to allow the product to precipitate. The product was collected by filtration and washed with water. An extraction was performed on the filtered product with ether and water. The product was a white powder and its purity was determined by HPLC. HPLC conditions: 50% acetonitrile in water, 10mM ammonium acetate buffer/ acetic acid, pH 4.5, Luna C18 column 250 x 4.6mm, flow rate 1.5 mL/min. The Product peak was observed at 4.2 mins. The purity of the product was approximately 98%, determined by HPLC. Calculated yield: 57.8%. The identity of the product was confirmed by 1H NMR and mass spec. Figure 1: Synthesis of [12C]N-Methyl Lansoprazole Unlabeled Reference Standard 2.2 Synthesis of [11C]N-Methyl Lansoprazole Following production of the reference standard, the methylation had to be adapted for use with carbon-11. A GE FX C Pro carbon-11 synthesis module was used to perform all radiochemistry. In order to label the lansoprazole precursor, 11CH3-methyltriflate was reacted with the lansoprazole precursor in the synthesis module (see figure 2). This reaction was performed using the loop method6. Figure 2: Synthesis of [11C]N-Methyl Lansoprazole 2.2.1 production of [11C]CH3OTf All procedures were done using a General Electric Medical Systems Tracerlab FXc Pro synthesis system. A 30 minute beam from a GE PetTrace cyclotron was used to convert a nitrogen gas target to carbon-11 which rapidly reacted with atmospheric oxygen to form [11C]CO2 . [11C]CO2 was delivered from the target via a 1/16” Teflon delivery line by nitrogen pressure directly to a column packed with 0.3g of molecular sieve and 0.2g of Shimalite –Nickle where it was trapped at room temperature. The column was then sealed under hydrogen gas (atmospheric pressure) and heated to 350oC for 20 seconds to reduce the [11C]CO2 to [11C]CH4. The [11C]CH4 was passed through a column of phosphorous pentoxide desiccant and trapped on a column of carbosphere at -78oC. Gaseous [11C]CH4 was released by heating the carbosphere column to 80 oC. Once released the methane entered a circulation loop, which included a gas pump, column of iodine at 100oC, the Tracerlab standard iodine reactor tube at 720oC, two adjacent columns of Ascarite II and a column of Porapak Q at room temperature. The gaseous mixture was circulated for 5 minutes while [11C]MeI accumulated on the Porapak column. [11C]MeI was released from the Porapak column by heating the, and passed over a column of silver triflate (heated to 190oC) to generate [11C]CH3eOTf. [11C]CH3OTf was then delivered to the awaiting reaction loop. 2.2.2 reaction of lansoprazole with [11C]CH3OTf One milligram of lansoprazole precursor was dissolved in 0.2 mL of THF and injected into the HPLC reaction loop of the synthesis module. [11C]CH3MeOTf was then passed through the reaction loop at a flow rate of 10 mL/min for 5 minutes. Following this reaction, the product was passed through a Luna C8 HPLC column (250x10mm) using a 35% acetonitrile in 10mM ammonium acetate buffer (pH 4.5). The peak at 17 minutes was collected into 50 mL of water and passed through a C-18 extraction cartridge to remove HPLC solvent, and then eluted with 0.5 mL of ethanol followed by 4.5 mL of saline. The final dose was filtered with a 0.22 um sterile filter. Analytical HPLC was conducted for quality control purposes using a Luna C18 column (250x4.6mm) with a 50% acetonitrile in 10mM ammonium acetate buffer solution (pH 4.5). A co-injection with the reference standard was performed to confirm the identity of the radiochemical product. The final purified radiotracer activity was approximately 85 milicuries. 3. Discussion [11C]N-Methyl Lansoprazole was successfully synthesized according to the description above. Radiochemistry, unlike traditional organic chemistry, is very time sensitive due to the short half-life of carbon-11. Because the half-life of carbon-11 is only 20 mins, it is essential that the entire reaction and purification takes as little time as possible in order to preserve the maximum amount of radioactivity for PET scanning. The quick reaction time and relatively high yield synthesis makes [11C]N-Methyl Lansoprazole a prime candidate for further testing and development. The next step in this research will be the implementation of this drug in rodent and primate studies to determine the compound’s biodistribution in the body and its effectiveness as a tau marker. Rodent and primate models will first be used to determine the compound’s ability to pass into the brain through the blood brain barrier. In order to do this, a dose of the drug will be injected into an animal that will then undergo a whole body PET scan to look at how much activity enters the brain. If the dug can effectively pass through the blood brain barrier, further in vivo and in vitro experiments will be conducted to determine the drugs ability to bind specifically with NFTs. 4. Acknowledgements The authors wish to express their appreciation to the Department of Energy (DOE) and National Institute of Health (NIH) for funding and to Dr. Xia Shao for her help with radiochemical syntheses. 5. References 1 Lee, Virginia M-Y, Goedert, Michael, Trojanowski, John Q. 2001. Neurodegenerative Tauopathies. 2 Rojo, Leonel E., Alzate-Morales, Jans, Saavedra, Ivan N., Davies, Peter, Maccioni, Ricardo B. 2010. Selective Interaction of Lansoprazole and Astemizole with Tau Polymers: Potential New Clinical Use in Diagnosis of Alzheimer’s Disease. Journal of Alzheimer’s Disease. 19, 573-589. 3 For reviews, see: a) F. Y. J. Keng. “Clinical Applications of Positron Emission Tomography in Cardiology: A Review” Ann. Acad. Med. Singapore 33 (2004): 175; b) S. Furst. PET (Positron Emission Tomography) in Cardiology. MTA 14 (1999): 506. 4 For reviews, see: a) J. R. Mercer. “Molecular Imaging Agents for Clinical Positron Emission Tomography in Oncology other than Fluorodeoxyglucose (FDG): Applications, Limitations and Potential” J. Pharm. Pharm. Sci. 10 (2007): 180; b) N. Oriuchi, T. Higuchi, T. Ishikita, M. Miyakubo, H. Hanaoka, Y. Iida, K. Endo. “Present Role and Future Prospects of Positron Emission Tomography in Clinical Oncology” Cancer Sci. 97 (2006): 1291; c) D. Le Bars. “Fluorine-18 and Medical Imaging: Radiopharmaceuticals for Positron Emission Tomography” J. Fluorine Chem. 127 (2006): 1488; d) A. M. Scott. “PET Imaging in Oncology” in Positron Emission Tomography: Basic Sciences (Eds.: D. L. Bailey, D. W. Townsend, P. E. Valk, M. N. Maisey), (2005): 311; e) H. Fukuda, S. Furumoto, R. Iwata, K. Kubota. “New Radiopharmaceuticals for Cancer Imaging and Biological Characterization using PET” Int. Congr. Ser. 1264 (2004): 158. 5 For reviews, see: a) A. Nordberg. “PET imaging of amyloid in Alzheimer's disease” Lancet Neurol 3 (2004): 519; b) L. Cai, R. B. Innis, V. W. Pike. “Radioligand Development for PET Imaging of β-Amyloid (Aβ)-Current Status” Curr. Med. Chem. 14 (2007): 19; c) R. M. Cohen. “The Application of Positron-Emitting Molecular Imaging Tracers in Alzheimer’s Disease” Mol. Imaging Biol. 9 (2007): 204; d) C. Wu, V. W. Pike, Y. Wang. “Amyloid Imaging: From Benchtop to Bedside” Curr. Top. Dev. Biol. 70 (2005): 171; e) R. Sanchezpernaute, A. L. Brownell, B. G. Jenkins, O. Isacson. “Insights into Parkinson's disease models and neurotoxicity using non-invasive imaging” Toxicol. Appl. Pharmacol. 207 (2 - Suppl. 1) (2005): 251. 6 Shao, Xia, Kilbourn, Michael. 2009. A simple modification of GE tracerlab FX C Pro for rapid sequential preparation of [11C]carfentanil and [11C]raclopride. Applied Radiation and Isotopes. 67, 602-605.

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