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9/28/2012 Take home lessons: What you should learn from todays lecture Chelate chemistry for molecular imaging • Choose the proper ligand for a particular metal ion. Why is this important? A. Dean Sherry, PhD • Macrocyclic ligands versus acylic ligands: pros & cons Professor of Chemistry, University of Texas at Dallas Director, Advanced Imaging Research Center, University of Texas Southwestern Medical Center • Which is more important for metal chelate applications in vivo? Thermodynamics or kinetics Professor of Radiology, UT Southwestern Medical Center WMIC, Dublin, Sept 5, 2012 Ligands Some common ligands used for chelating metal ions Chelates versus A ligand is defined as any anion or organic molecule that donates a pair of electrons to a metal ion. Acyclic ligands Macrocyclic ligands HO2C N N N N HOOC CO2H HO2C N N CO2H HO2C N O2C HO2C - O2C CO2H HO2C Ethylenediaminetetraacetate (EDTA) a hexadentate ligand Nitrilotriacetate (NTA) classic example of a tetradentate ligand • The resulting ML complexes are called chelates. HN R N N N N CO2H DO3A-monoamide N HO2C N N O HO2C DOTA side-arm version N N N N CO2H H N R HO2C NOTA backbone version HO2C N HO2C HO2C CO2H N N N N N N CO2H H R N HN R S PCTA backbone version O HN R HOOC HOOC COOH N HOOC OH N H2N O O O N H N OH desferrioxamine HO2C N N O N OH N O N N HO2C NETA Question: So, with all these choices, how does one choose the best ligand or bifunctional ligand for your particular molecular imaging application? Answer: NH N R H CB-TETA side-arm version CHX-DTPA CO2H PCTA HO2C S HO2C HN N N CO2H DOTA backbone version N HO2C CO2H Bifunctional ligands are widely used to attach a ligand to a targeting moiety bifunctional chelates (BFC) NH CO2H N HO2C N N HO2C NOTA N CB-TE2A Typical chelates Gd(DTPA)268Ga(NTA) Fe(EDTA)- O HO2C N COOH DTPA CO2H NH H N R N N N COOH S H R N HO2C HO2C O N N CO2H Bifunctional ligands are widely used to attach a ligand to a targeting moiety bifunctional chelates (BFC) N CO2H N Multidentate ligands bind to a metal ion by displacing solvent molecules (often water) to form a ML complex • Multidentate ligands are called chelating agents (claw). N TETA CO2This version of “cis-Pt” has one bidentate ligand (en) and two monodentate ligands (Cl-) N COOH N N HO2C DOTA N “cis-platinum” has two types of monodentate ligands, :NH3 and Cl- HO2C HO2C CO2H N HOOC - N N COOH N HOOC COOH DTPA backbone version N N COOH O COOH • • • • It depends! On size matching of metal ion and ligand cavity Thermodynamics (how stable does the chelate need to be?) Kinetics of ML complex formation Charge on resulting chelate; perhaps it needs to be charged or neutral DTPA monoamide 1 9/28/2012 Some common radionuclides and ligands used in molecular imaging Imaging Modality Most common metal ion Most common ligand(s) MRI Gd3+ DOTA-like, DTPA-like 8-coordinate, needs one water site, prefers “hard” donor atoms PET 64Cu2+ cyclen, DOTA, TETA, bridged TETA, NOTA Prefers N donors, only 4 coordinate necessary 68Ga3+ DOTA, NOTA Prefers octahedral and “hard” donor atoms SPECT Ligand characteristics • Selection of ligand donor atoms (coord #, donor types) 86Y3+ DOTA-like 8-9 coordinate like Gd3+ 89Zr2+ Desferrioxamine-like “hard” oxygen donors 99mTc2+ Methoxyisobutylisonitrile (Sestamibi) N donor atoms 111In3+ DTPA-like 8-coordinate, somewhat “softer” ion Factors to consider in the design of ligands for various metal ions • HSAB principles, matching coordination numbers • Role of ligand architecture (cyclic versus acyclic) • Limited to size-match selectivity • Kinetics of ML complex formation & dissociation • Ligands with flexible backbone structures form complexes more quickly but also dissociate faster • Macrocyclic ligands form complexes more slowly but also dissociate more slowly Hard-Soft Acid-Base Principles (HSAB) Size does matter! Ligand donor types (from softest to hardest): P < S < N < O < F For 3d transition metal ions 21 Sc 22 Ti 23 V 24 Cr 25 Mn 26 Fe 27 Co 28 Ni 29 Cu 30 Zn HO2C 1) M2+ ions get smaller and harder from left to right (increasing nuclear charge) N N N N HO2C Ti2+ (86 pm) > V2+ (79 pm) > Cr2+ (73 pm) > Mn2+ (67 pm) > Fe2+ (61 pm) CO2H HO2C N N CO2H N CO2H HO2C DOTA NOTA 2) M+ (softer) < M2+ (intermediate) < M3+ (harder) V2+ (79 pm) >> V3+ (64 pm) >> V4+ (53 pm) Gd3+ (4f7) ionic radius ~1.0Å log Kst = 24.7a Ga3+ (3d10) ionic radius ~0.6Å log Kst = 21b, 26c As one progresses down a series (3d 4d 5d) for ions of the same charge 22 Ti hardest 25 Mn hardest 30 Zn hardest 40 Zr intermed. 43 Tc intermed. 48 Cd intermed. 72 Hf softest 75 Re softest 80 Hg softest aWP kf,HL kd,HL Potentiometry is considered the“gold standard” 12 12 LnL + H+ K ST K HL [ L] [ H ] [ HL] et al., Inorg. Chem., 49, 10960-10969 (2010) Thermodynamic Stability Constant Determinations: 100 10.5 10.5 Kcond = conditional stability constant (defined by conditions, i.e., pH) [ LnL] [ Ln 3 ] [ L] & Martell, Inorg. Chimica Acta, 181, 273-280 (1991) cKubicek, Fraction of Y3+ species Ln3+ + HL 99 pH 7.5 7.5 Y3+ 80 Y3+L 60 p-NO22-Bz-DOTA -Bz-DOTA p-NO 40 typical curve curve for for fast fast typical ML formation formation ML 2+ M2+ p-NO22-Bz-DOTA -Bz-DOTA M :: p-NO (log K KML =23.5) (log ML=23.5) 20 0 1.5 2 2.5 pH 66 4.5 4.5 33 Thermodynamic ML stability constant Highest pKa of the ligand (most basic site) the reverse rxn is referred to as the first protonation step or constant log Kst = 31b Cacheris, SK Nickle & AD Sherry, Inorg Chem, 26, 958-960 (1987) bClark Some basic definitions: thermodynamic constants, kinetic constants, pKa’s and basicity log Kst = 14.3a 3+ Y : slow kinetics (log KML=23.9) 1.5 1.5 00 22 44 66 88 10 10 Base equivalents 2 9/28/2012 CO2- -O2C N N N N Ligand charge also plays a role CO2- -O2C CO2- -O2C N N N -O CO2- -O -O2C CO2N 2C N N N N 2C CO2 - CO2 - -O -O 2C N log Kst (Gd3+) N N N N CNHCH2 CH 2 CH 3 CO2 - -O -O 2C N N N CO2 - CO2 - DO3A-SA 20.1b 24.7a N 2C DO3A-Npropylamide CO2- -O2C N 2C DOTA N -O2C CO2- O CO2- -O2C -2 O -2 O 3P N N N N 3P PO3 -2 PO3 -2 DOTP 27.2c 28.8d CO2- N aWP Cacheris, SK Nickle & AD Sherry, Inorg Chem, 26, 958-960 (1987) Sherry, RD Brown, CFGC Geraldes, SH Koenig, K-T Kuan & M Spiller, Inorg Chem., 28, 620-622 (1989) Andre, E Brucher, R Kiraly, RA Carvalho, H Maecke, CFGC Geraldes, Helv. Chim. Acta, 88, 633 (2005). Sherry, J Ren, J. Huskens, E Brucher, E. Toth, et al. Inorg. Chem. 1996,35, 4604 (1996) bAD cJP -O2C dAD WP Cacheris, SK Nickle & AD Sherry, Inorg Chem, 26, 958-960 (1987) Correlation of kf,HL, kd,H, and log KML with the first protonation constant of the ligand (log KHL) kf,HL Keq K ST LnL + H+ kd,HL [ LnL] [ H ] k f , HL K ST K HL [ Ln 3 ] [ HL] k d , H k f , HL log K ST k d , H K HL k f , HL kd ,H log KST Ln3+ + HL log KST vs ΣpKa’s for a series of GdL complexes pK a From: WP Cacheris, SK Nickle & AD Sherry, Inorg Chem, 26, 958-960 (1987) A more recent compilation: Brücher, et al., “Stability and Toxicity of Contast Agents”, Chapter 5, in The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, edited by Merbach, Toth & Helm, Wiley, 2012. Importance of kinetics: rates of ML formation 30 DO3AP DOTA-SA 26 DOTA log K Gd(L) p-NO2 -Bz-DOTA DO3A-nBuAm 2HE-DO2A PC2A kd,HL LnL + H+ DOTEP Ln3+aq DOTAM DTMA DOTA-4Gly NOTA fast 10 15 kf,HL TRITA BT-DO3A BP2A Ln3+ + HL Why do macrocyclic ligands form complexes with metal ions so slowly? DO2A p-NO 2 -Bz-PCTA 14 DOTP DOA3P DO2A2P DO3A PCTA 18 DO3MA DO3APABn HP-DO3A 2HP-DO2A DO3A-Pic 22 DO3APPrA 17 19 21 H log K 1 + log K 2 23 H slow, requires deprotonation 25 H2DOTA (pre-organized) Intermediate LnH2DOTA Fully formed LnDOTA 3 9/28/2012 Correlation of kf,HL with the first protonation constant of the ligand (log KHL) The three bifunctional ligands were conjugated to trastuzumab log kf,HL 8 4 10,5 oxo & pcta, 0.5 mg HP-DO3A HE-DO3A The oxo and pcta derivatives form complexes with 64Cu2+ much more quickly than dota HIP-DO3A DO3A dota, 0.1 mg 12-membered ring, acetate systems 11 dota, 0.5 mg oxo, 0.1 mg pcta, 0.1 mg DOTA 6 5 CL Ferreira, DTTT Yapp, S Crisp, et al., Eur J Nucl Med Mol Imaging 37: 2117-2126 (2010) CuDOTA only moderately stable in vivo; CuNOTA and Cu-CB-TETA more stable but they also form complexes too slowly for efficient antibody labeling 9 7 Comparison of bifunctional chelates for 64Cu2+-antibody imaging 11,5 12 12,5 13 DO3MA 13,5 log pKKaHL Transverse PET images at 24 h (top) and 40 h (bottom) post-injection for each 64Curadiolabeled BFC-trastuzumab conjugate in LCC6Vector or LCC6HER2 tumor-bearing mice. K. Kumar and M. F. Tweedle, Inorg. Chem., 1993, 32, 4193-4199 Increased backbone rigidity improves the kinetic stability of complexes Are LnDOTA-tetraamide complexes safe for in vivo use? Gd(AZEP-DTPA) Gd(PIP-DTPA) AZEP-DTPA Gd(DTPA) PIP-DTPA H-S Chong, K Garmestani, LH Bryant, Jr., MW Brechbiel, J Org Chem, 66, 7745-7750 (2001) Take home lessons: • Why it is important to choose the proper ligand for a particular metal ion for molecular imaging. • Ligand size and donor type should match the characteristics of the metal ion • Macrocyclic ligands versus acylic ligands: • Macrocyclic ligands form more stable ML chelates but they also form more slowly (this kinetic barrier may be important in radiolabeling of antibodies which cannot be heated) • Which is more important for metal chelate applications in vivo? • Thermodynamics is important but kinetics is likely even more important for in vivo applications! Thanks • To my many students, postdocs & collaborators Prof. Zoltan Kovacs, Prof. Mark Woods, Bill Cacheris, Garry Kiefer, Prof. Gyula Tirsco, Won-dae Kim, Prof. Jimen Ren, Prof. Istvan Lazar, Shanrong Zhang, Prof. Carlos Geraldes, Prof. Jurriaan Huskens, Flavio Chavez, Prof. Navin Bansal, Yunkou Wu and, especially, Prof. Erno Brücher (Hungary) who taught me how to do potentiometry well. • Acknowledgements: Financial support from NIH grants RR-02584, CA-115531, CA-126608, EB-004582 and the Robert A. Welch Foundation (AT-584). 4