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Medicinal Chemistry: Technetium and Nuclear Medicine

Medicinal Chemistry: Technetium and Nuclear Medicine

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Medicinal Chemistry: Technetium and Nuclear Medicine

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  1. Medicinal Chemistry:Technetium and Nuclear Medicine ICIS - CNR - Padova, Italy

  2. Group 7 metals relevant to Nuclear Medicine - 1 4 5 6 7 8 9 10 11 Ti V Cr Mn Fe Co Ni Cu 1st row Ag Zr Nb Tc Pd Rh Ru Mo 2nd row Ir Hf Ta W Re Os Pt Au 3rd row transition metals

  3. radiometabolic theraphy • 188Ret1/2 = 16.9 h • Eb- = 2.0 MeV • 186Ret1/2 = 90.0 h • Eb- = 1.1 MeV • radiodiagnosis • 99mTct1/2 = 6.0 h • Eg = 142 keV • inorganic chemistry • 99Tct1/2 = 2.12x105 y • Eb- = 292 keV • inorganic chemistry • ’cold’ 185/187Re Group 7 metals relevant to Nuclear Medicine - 2

  4. Inorganic Chemistry vs Nuclear Medicine • inorganic chemistry:10-3 – 10-5 M (millimolar conc) • Conventional physico-chemical characterization • NMR, IR, UV-vis spectroscopies • Mass spectrometry (EI, ESI) • X-ray crystal structure determination • TLC & HPLC chromatography • nuclear medicine:10-7 – 10-9 M (micro/nanomolar conc) • Radiometric characterization • TLC & HPLC chromatography

  5. The 99Mo/99mTc generator 99Mo t1/2 = 66.7 h; Eb- = 1.37 MeV 99mTc t1/2 = 6 h; Eg- = 142 KeV 99Tc

  6. The bifunctional approach in mixed nitrido-Tc heterocomplexes O H H N N N P S O Tc P O N S N H O MW = 913

  7. N N Tc Tc P P Cl Y Cl P P Z X X The substitution-inert [Tc(N)(PXP] synthon Bolzati et al.,J. Am. Chem. Soc. 124, 2002, 11468

  8. Crystal structure of [Re(N)(dedc)(pnp2)]+ • pseudo-octahedron • cis-P co-ordination • P(1)-Re-P(2) = 101.2(1)° • trans-N co-ordination • N(1)-Re-N(2) = 164.5(5)° • Re-N(2) = 2.73(1) Å

  9. S P P N N S O dedc pnp2 O O O P P S O N O N S O O dbodc pnp5 From aryl- to alkyl-diphosphines

  10. 846.6 100 95 90 85 [Tc(N)Cl2(PPh3)2] 80 75 i) pnp5 ii) dbodc DCM 70 65 60 55 Relative Abundance yellow oil 50 45 40 35 30 25 20 848.6 15 10 640.6 527.4 849.5 5 844.7 279.4 552.8 306.5 641.6 371.4 862.5 413.5 788.5 185.3 130.6 961.8 1049.9 1139.0 1183.9 1314.2 1401.2 1454.4 0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 m/z ESI - MS of [99Tc(dbodc)(pnp5)]+ M+ E. Marotta et al, RCM, 2003, submitted

  11. 640.3 100 95 90 85 80 75 70 65 641.3 60 55 Relative Abundance 50 45 40 35 30 847.4 25 668.2 20 846.4 15 669.3 553.2 10 569.2 527.2 405.1 348.0 582.3 608.3 5 813.3 406.1 844.3 297.1 775.3 276.0 318.0 452.3 496.1 758.2 714.5 868.9 0 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000 m/z Collisional experiments on [99Tc(N)(bdodc)(pnp5)]+ -MS2 - -

  12. 594.2 100 95 90 85 80 75 403.0 70 65 60 55 Relative Abundance 50 45 40 35 30 25 20 640.2 15 568.2 10 435.0 608.2 401.1 527.0 331.0 5 493.1 566.1 284.7 247.8 462.2 227.2 865.4 640.9 914.8 0 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000 m/z Collisional experiments on [99Tc(N)(bdodc)(pnp5)]+ -MS3 - - -

  13. Collisionally induced fragmentation pattern of [99Tc(N)(dbodc)(pnp5)]+

  14. 99Tc-complex 1H NMR of [99Tc(N)(dbodc)(pnp5)]+ O S N S O dbodc O O P P O N O O pnp5

  15. dbodc N-CH2-CH2-O- dbodc -O-CH2-CH3 pnp5 N-CH2-CH2-O- pnp5 -O-CH2-CH3 1H-1H COSY-45 of [99gTc(N)(dbodc)(pnp5)]+

  16. -O-CH3 -C-CH3 various CH2 31P and 13C NMR of [99Tc(N)(dbodc)(pnp5)]+ 30.2 ppm impurity oxidized pnp5

  17. C-CH3 C-C and P-C N-C region O-CH3 O-C region 1H - 13C HMQC of [99Tc(N)(dbodc)(PNP5)]+ + O O N O O P S N Tc O O S P N O P-…CH2-O-

  18. 99mTc-DBODC5 99mTc-Cardiolite 99mTc-Myoview Nitrido-99mTc(V) hetero-complexes:heart uptake in rats 6 5 %ID/g 4 3 2 1 2 5 10 20 30 60 120 time (min) A. Boschi et al.,J. Nucl. Med. 2003, in press

  19. 35 99mTc-DBODC5 30 99mTc-Cardiolite 25 h/l 99mTc-Myoview 20 15 10 5 2 5 10 20 30 60 120 Nitrido-99mTc(V) hetero-complexes:heart/liver ratio in rats time (min)

  20. Nitrido-99mTc(V) hetero-complexes:micro-SPET analysis

  21. Cardiolite® by Dupont NOEt by Cis-Schering Tc(N)DBODC5 by Nihon Medi-Physics Nitrido-99mTc(V) hetero-complexes:micro-SPET analysis