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Synthesis of isotopically labelled [ 14 C]ZT-1, [d 3 ]ZT-1 & (-)-[d 3 ]huperzine A, a new generation of acetylcholinesterase inhibitors Dr Sean Kitson.

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Presentation on theme: "Synthesis of isotopically labelled [ 14 C]ZT-1, [d 3 ]ZT-1 & (-)-[d 3 ]huperzine A, a new generation of acetylcholinesterase inhibitors Dr Sean Kitson."— Presentation transcript:

1 Synthesis of isotopically labelled [ 14 C]ZT-1, [d 3 ]ZT-1 & (-)-[d 3 ]huperzine A, a new generation of acetylcholinesterase inhibitors Dr Sean Kitson ШОН КИТСОН

2 Objective This lecture will focus on a brief introduction to carbon-14 Leading onto synthetic strategies towards labelling (-)-huperzine A derivatives with 14 C and 2 H

3 cpres/v1b/ca/ /3 A Brief Introduction to 14 C

4 Discovery of 14 C Martin Kamen & Sam Ruben (27-FEB-1940) T 1/2 ~ 5730 Years

5 Production of 14 C Reactor Bombardment by Neutrons Nitrogen 14 7 Protons 7 Neutrons N P P Radioactive atom Carbon 14 6 Protons 8 Neutrons Decay to stable daughter nuclide Nitrogen 14 7 Protons 7 Neutrons N ß- P P 14 N n 0 14 C H 1

6 14 C Starting Materials Ba(OH) 2

7 Barium 14 C carbonate staircase R T Brown et al. JLCR 2009, 52, S L Kitson, S Jones et al. JLCR 2010, 53, S L Kitson. JLCR 2007, 50, S L Kitson, E Knagg. JLCR 2006, 49, [ 14 C]Apomorphine[ 14 C]Combretastatin A-1 [ 14 C]XEN-D0401 [ 14 C]Acetylenes

8 14 C Labelling When designing a 14 C labelled synthesis it is important to consider the following: Identify simple starting materials from the barium 14 C carbonate staircase which are commercially available or alternatively easily made Plan, develop and execute the synthetic methodology to the final drug substance. This approach can often restrict the position of the label in the drug and will cause a change in the drug purity profile from the original laboratory synthesis route Locate a biologically stable position for the 14 C label S L Kitson Accelerated Radiochemistry,PMPS Manufacturing 2010, 68-70

9 14 C Drug Molecules 14 C Labelled drugs are used in human mass balance or AME studies to evaluate: Mass balance and the routes of elimination Identify circulatory and excretory metabolites Determination of clearance mechanisms To determine the exposure of parent compound and its metabolites Used to validate animal species used for toxicological testing To explore whether metabolites contribute to the pharmacological / toxicological effects of the drug C Prakash et al. Biopharm. Drug Dispos; 2009, 30,

10 (-)-Huperzine & ZT-1

11 (-)-Huperzine A (-)-Huperzine A is a naturally occurring Lycopodium alkaloid found in an extract from the club moss Huperzia serrata (-)-Huperzine A is a potent, selective and reversible inhibitor of acetyl cholinesterase, the enzyme that breaks down or degrades acetylcholine (-)-Huperzine A is currently a prescription medication in China for the treatment of Alzheimer's Disease C M Yu et al. Canadian J Chem 1986, 64, D L Bai et al. Curr. Med. Chem; 2000, 7,

12 ZT-1: Pro-drug for (-)-Huperzine A A Novel Acetylcholinesterase Inhibitor L Leman, S L Kitson, R T Brown et al. JLCR 2011 (in press)

13 ZT-1 Implant S. Capancioni et al. Preparation of a sustained-release implant of the acetylcholinesterase inhibitor ZT-1 by hot-melt extrusion (HME) and evaluation in rats Debiopharm (April 2006)

14 ZT-1 implant offers the following advantages over oral ZT-1: Once-a-month dosing Implant-controlled progressive increase in (-)-huperzine A plasma levels Sustained plasma levels A prolonged release of the (-)-huperzine A over several weeks S. Capancioni et al. Preparation of a sustained-release implant of the acetylcholinesterase inhibitor ZT-1 by hot-melt extrusion (HME) and evaluation in rats Debiopharm (April 2006)

15 [ 14 C] & [d 3 ] - Targets

16 Synthesis of [ 14 C]ZT-1 14 C labelling

17 Schiff base

18 Retro-synthetic pathway

19 14 C Synthesis * = U- 14 C

20 [ 14 C]ZT-1

21 Synthesis of [d 3 ]ZT-1 & (-)-[d 3 ]huperzine

22 Retro-synthesis

23 Synthesis of (-)-[d 3 ]huperzine A C. Ferreri et al. Chem. Commun; 1999,

24 Synthesis of (-)-[d 3 ]huperzine A G A Olah, J. Org. Chem; 1979, 44, S-I Yamada et al. J. Am. Chem. Soc; 1972, 94, 6203

25 Synthesis of [d 3 ]ZT-1 & reduced-[d 3 ]ZT-1

26 Conclusion [ 14 C]ZT-1 was isolated with a radiochemical purity of >98%area and a gravimetric specific activity of 129 μCi/mg in a seven step synthesis starting from [U- 14 C]phenol in 7% yield Subsequently, the deuterium labelled target (-)-[d 3 ]huperzine A was achieved in 6 steps with an overall yield of 15% and gave an isotopic distribution of d 2 (1.65% huperzine A) and d 3 (97.93% huperzine A) with a chemical purity of 98.5%

27 Conclusion Condensation of the substrate (-)-[d 3 ]huperzine A with 5-chlorovanillin gave the Schiffs base [d 3 ]ZT-1 in a chemical yield of 80% Reduction of the Schiffs base gave reduced-[d 3 ]ZT-1 which was converted into the hydrochloride salt with an isotopic distribution of d 2 (1.60%) and d 3 (98.02%)

28 Almacs Radiochemistry Laboratory

29 Almacs Radiolabelling Team

30 Non GMP API Manufacture Drug Product Manufacture GMP API Manufacture Form.Dev. Clinical Packaging and Labelling RadioLabelling Solid State & Analytical Services Stability Biomarkers & Diagnostics DiscoveryResearch IVRS Northern Ireland HQ (32 acre site ) Confidential © Almac Group 2010

31 North American HQ (40 acre site) Clinical Packaging & Distribution Admin & Clinical Tech Facility Solid State & Analytical Services

32 Thank you / Спасибо The hexagonal shapes denote the famous Giants Causeway rock in Northern Ireland – these shapes also connect to the benzene ring used in science


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