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Development of Palladium- Promoted 11C/12C- Carbonylations and Radiosynthesis of Amyloid PET Ligands

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Development of Palladium- Promoted 11C/12C- Carbonylations and Radiosynthesis of Amyloid PET Ligands Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 183 Development of Palladium- Promoted 11C/12C- Carbonylations and Radiosynthesis of Amyloid PET Ligands PatriK NOrdEMAN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 UPPSALA ISBN 978-91-554-8843-7 2014 urn:nbn:se:uu:diva-213863 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husargatan 3, Uppsala, Friday, 21 February 2014 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor Antony D Gee (Division of Imaging Sciences, King's College, London). Abstract Nordeman, P. 2014. Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 183. 76 pp. Uppsala: Uppsala universitet. ISBN 978-91-554-8843-7. In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N- cyanobenzamide analogs of flufenamic acid and dazoxibene. In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)- mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid- binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases. Keywords: Palladium, Carbonylation, Positron emission tomography, PET, Carbon-11, Fluor-18, Radiochemistry, Amyloidosis Patrik Nordeman, Department of Medicinal Chemistry, Preclinical PET Platform, Dag Hammarskjöldsv 14C, Uppsala University, SE-751 83 Uppsala, Sweden. © Patrik Nordeman 2014 ISSN 1651-6192 ISBN 978-91-554-8843-7 urn:nbn:se:uu:diva-213863 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-213863) "A scientist in his laboratory is not a mere technician: he is also a child confronting natural phenomena that impress him as though they were fairy tales." Marie Curie (1867-1934) List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Nordeman, P., Odell, L. R., Larhed, M. (2012) Amino- carbonylations Employing Mo(CO)6 and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides. J. Org. Chem., 77(24): 11393- 11398. II Mane, R. S., Nordeman, P., Odell, L. R., Larhed, M. (2013) Palladium-catalyzed Carbonylative Synthesis of N- Cyanobenzamides from Aryl Iodides/Bromides and Cyanamide. Tetrahedron Lett. 54(51): 6912-6915. III Nordeman, P., Antoni, G., Odell. L. R. Pd-mediated Carbonyl- ative Synthesis of 11C-N-Cyanobenzamides. Manuscript. IV Wångsell, F., Nordeman, P., Sävmarker, J., Emanuelsson, R., Jansson, K., Lindberg, J., Rosenquist, Å., Samuelsson, B., Larhed M. (2011) Investigation of α-Phenylnorstatine and α- Benzylnorstatine as Transition State Isostere Motifs in the Search for New BACE-1 Inhibitors. Bioorg. Med. Chem. 19(1): 145-155. V Nordeman, P., Estrada, S., Odell, L. R., Larhed, M., Antoni, G. 11C Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo. Submitted. VI Nordeman, P., Johansson, L. B. G., Bäck, M., Estrada, S., Hall, H., Westermark, G. T., Westermark, P., Nilsson, L., Ham- marström, P., Nilsson, P., Antoni G. 11C and 18F Radiolabeling of Tetra and Pentatiophenes as PET-Ligands for Misfolded Pro- tein Aggregates. Manuscript. Reprints were made with permission from the respective publishers. Papers Not Included in This Thesis Datta, G. K., Nordeman, P., Dackenberg, J., Nilsson, P., Hallberg, A., Larhed, M. (2008) Enantiopure 2-aryl-2-methyl Cyclopentanones by an Asymmetric Chelation-controlled Heck Reaction Using Aryl Bromides: Increased Preparative Scope and Effect of Ring Size on Reactivity and Se- lectivity. Tetrahedron: Asymmetr. 19(9), 1120-1126. Strand, J., Nordeman, P., Honarvar, H., Altai, M., Larhed, M., Orlova, A., Tolmachev, V. Site-specific Radioiodination of HER2-targeting Affibody Molecules Using Iodophenetylmaleimide Decreases Renal Uptake of Ra- dioactivity. Manuscript. Contents Introduction ................................................................................................... 11 Palladium as a Catalyst in Organic Chemistry ......................................... 11 Carbonylative Palladium Chemistry ........................................................ 13 Towards Simpler Carbonylative Procedures ....................................... 16 Tracer Development in Positron Emission Tomography ......................... 18 Tracer Considerations .......................................................................... 19 Radiochemistry .................................................................................... 21 Palladium-Catalyzed Carbonylations using a Two Chamber System ........... 23 Synthesis of Benzamides (Paper I) ........................................................... 23 Background and Aim ........................................................................... 23 Results and Discussion ........................................................................ 24 Synthesis of N-Cyanobenzamides (Paper II) ............................................ 30 Background and Aim ........................................................................... 30 Results and Discussion ........................................................................ 30 Pd-mediated 11C-Carbonylative Synthesis of 11C-N-Cyanobenzamides (Paper III) ...................................................................................................... 36 Background and Aim ........................................................................... 36 Results and Discussion ........................................................................ 37 Amyloid Diseases - Enzyme Inhibitors and PET Tracers ............................. 43 Amyloid Diseases ..................................................................................... 43 Synthesis of BACE-1 Inhibitors Comprising α-Phenylnorstatine and α- Benzylnorstatine as Transition State Isosters (Paper IV) ......................... 46 Background and Aim ........................................................................... 46 Results and Discussion ........................................................................ 47 11C-Labeling of a Potent Hydroxyethylamine BACE-1 Inhibitor and Evaluation in vitro and in vivo (Paper V) ................................................. 52 Background and Aim ........................................................................... 52 Results and Discussion ........................................................................ 53 11C and 18F Radiolabeling of Tetra- and Penta-tiophenes as PET- Ligands for Amyloid Deposits (Paper VI) ............................................... 57 Background and Aim ........................................................................... 57 Results and Discussion ........................................................................ 58 Conclusions ................................................................................................... 65 Acknowledgements ....................................................................................... 67 References ..................................................................................................... 69 Abbreviations Aβ Amyloid beta AD Alzheimer's disease IAPP Islet amyloid polypeptide AL Amyloid light chain APP Amyloid precursor protein ATTR Transthyretin BACE-1 β-Secretase BBB Blood-brain barrier BOC tert-Butyloxycarbonyl Bmax Maximum binding capacity CNS Central nervous system CO Carbon monoxide CO2 Carbon dioxide CORM CO-releasing molecule CT Computed tomography DBU 1,8-Diazabicycloundec-7-ene
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