title: High relaxivity magnetic resonance imaging contrast agents. Part 1. Impact of single donor atom substitution on relaxivity of serum albumin-bound gadolinium complexes.
abstract: OBJECTIVE
  The donor atoms that bind to gadolinium in contrast agents influence inner-sphere water exchange and electronic relaxation, both of which determine observed relaxivity. The effect of these molecular parameters on relaxivity is greatest when the contrast agent is protein bound. We sought to determine an optimal donor atom set to yield high relaxivity compounds.
  
  
  METHODS
  A total of 38 gadolinium-1,4,7,10-tetraazacyclo-dodecane-N,N',N'',N'''-tetraacetato derivatives were prepared and relaxivity was determined in the presence and absence of human serum albumin as a function of temperature and magnetic field. Each compound had a common albumin-binding group and differed only by substitution of different donor groups at one of the macrocycle nitrogens. Oxygen-17 isotope relaxometry at 7.05 T was performed to estimate water exchange rates.
  
  
  RESULTS
  Changing a single donor atom resulted in changes in water exchange rates ranging across 3 orders of magnitude. Donor groups increased water exchange rate in the order: phosphonate ∼ phenolate > α-substituted acetate > acetate > hydroxamate ∼ sulfonamide > amide ∼ pyridyl ∼ imidazole. Relaxivites at 0.47 and 1.4 T, 37°C, ranged from 12.3 to 55.6 mM(-1)s(-1) and from 8.3 to 32.6 mM(-1)s(-1) respectively. Optimal relaxivities were observed when the donor group was an α-substituted acetate. Electronic relaxation was slowest for the acetate derivatives as well.
  
  
  CONCLUSIONS
  Water exchange dynamics and relaxivity can be predictably tuned by choice of donor atoms.
authors.affiliation: Epix Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dumas
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacques
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Sun
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Troughton
authors.forename: Joel T
authors.initials: JT
authors.lastname: Welch
authors.forename: Jaclyn M
authors.initials: JM
authors.lastname: Chasse
authors.forename: Heribert
authors.initials: H
authors.lastname: Schmitt-Willich
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
mesh_terms: D000418:Albumins / Q000737:chemistry*; D003287:Contrast Media / Q000737:chemistry* / Q000378:metabolism; D005682:Gadolinium / Q000097:blood* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*; D011485:Protein Binding
chemical_list: D000418:Albumins; D003287:Contrast Media; D005682:Gadolinium
references.citation: Magn Reson Med. 1991 Dec;22(2):339-42; discussion 343-6
references.pmid: 1812368
references.citation: Inorg Chem. 2004 Oct 4;43(20):6313-23
references.pmid: 15446878
references.citation: Invest Radiol. 2008 Feb;43(2):141-4
references.pmid: 18197066
references.citation: Inorg Chem. 2007 Jun 25;46(13):5260-70
references.pmid: 17539632
references.citation: Angew Chem Int Ed Engl. 2003;42(47):5889-92
references.pmid: 14673928
references.citation: Inorg Chem. 2007 Aug 6;46(16):6632-9
references.pmid: 17625839
references.citation: Invest Radiol. 2010 Sep;45(9):507-12
references.pmid: 20697223
references.citation: J Org Chem. 2003 Apr 4;68(7):2956-9
references.pmid: 12662076
references.citation: Invest Radiol. 1998 Nov;33(11):779-97
references.pmid: 9818313
references.citation: Chemphyschem. 2005 Dec 9;6(12):2570-7
references.pmid: 16294353
references.citation: J Am Chem Soc. 2004 Aug 4;126(30):9248-56
references.pmid: 15281814
references.citation: Inorg Chem. 2003 Jun 30;42(13):3972-4
references.pmid: 12817950
references.citation: Invest Radiol. 2008 Dec;43(12):861-70
references.pmid: 19002058
references.citation: J Am Chem Soc. 2002 Mar 27;124(12):3152-62
references.pmid: 11902904
references.citation: Chem Soc Rev. 2006 Jun;35(6):512-23
references.pmid: 16729145
references.citation: J Magn Reson. 2003 Jun;162(2):229-40
references.pmid: 12810007
references.citation: J Biol Inorg Chem. 2000 Aug;5(4):488-97
references.pmid: 10968620
references.citation: Invest Radiol. 2010 Oct;45(10):613-24
references.pmid: 20808234
references.citation: Invest Radiol. 2006 Mar;41(3):229-43
references.pmid: 16481905
references.citation: Dalton Trans. 2005 Dec 21;(24):3829-37
references.pmid: 16311635
references.citation: Chem Rev. 1999 Sep 8;99(9):2293-352
references.pmid: 11749483
references.citation: J Am Chem Soc. 2006 Jun 21;128(24):7807-16
references.pmid: 16771494
references.citation: Chemphyschem. 2006 Jul 17;7(7):1590-7
references.pmid: 16810729
references.citation: J Am Chem Soc. 2002 Jan 30;124(4):710-6
references.pmid: 11804502
references.citation: Inorg Chem. 2007 Apr 30;46(9):3576-84
references.pmid: 17425306
references.citation: Contrast Media Mol Imaging. 2006 May-Jun;1(3):128-37
references.pmid: 17193689
references.citation: J Am Chem Soc. 2001 Aug 8;123(31):7601-9
references.pmid: 11480981
references.citation: Chemistry. 2002 Mar 1;8(5):1040-8
references.pmid: 11891890
references.citation: Dalton Trans. 2007 Jan 28;(4):493-501
references.pmid: 17213936
references.citation: J Med Chem. 2002 Aug 1;45(16):3465-74
references.pmid: 12139457
references.citation: Inorg Chem. 2001 Dec 17;40(26):6580-7
references.pmid: 11735466
references.citation: Nucleic Acids Res. 1984 May 25;12(10):4051-61
references.pmid: 6728676
references.citation: Chemistry. 2008;14(24):7250-8
references.pmid: 18601236
references.citation: Acc Chem Res. 2009 Jul 21;42(7):893-903
references.pmid: 19537782
references.citation: Chemistry. 2005 Apr 8;11(8):2373-84
references.pmid: 15685711
references.citation: Chem Rev. 2005 Jun;105(6):1923-59
references.pmid: 15941206
references.citation: Contrast Media Mol Imaging. 2009 Mar-Apr;4(2):89-100
references.pmid: 19177472
references.citation: Acc Chem Res. 2009 Jul 21;42(7):822-31
references.pmid: 19534516
references.citation: Invest Radiol. 2010 Oct;45(10):662-8
references.pmid: 20733508
references.citation: Kidney Int. 2007 Aug;72(3):260-4
references.pmid: 17507905
references.citation: Chemistry. 2003 Nov 21;9(22):5468-80
references.pmid: 14639630
references.citation: Acc Chem Res. 2009 Jul 21;42(7):938-47
references.pmid: 19505089