Polymeric metal chelate magnetic resonance imaging
contrast agents
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MRI X- (CT), 1 !"#$%&' ()*+,-./)*0123 &456789:5.;<:= >?!"@ X- (CT)ABCDEFG&9HIJ &KLMNO$KPQR1ST MRI UVWX#YG&9HUZBL,[H\]RJ9,!^_`a spin-lattice(T1) b/c(T2)defg\hi"jkG9HRlm&de 2-51Fn!" opqrsNtWrsg\uvwxqyzg{|U}G9 Hde0,~1U!By1~f0 T1N T2a HM]R J"N20 T2]RJ9 nUZ>y\wxaHM J+1de JNGH1t uvjNuv` ¡!¢#Y% £+]RJ9¤¥¦§¨©\q+` ª T21n«¬®¤ #Y% aHM]R J¯&1°±²³ Gd ´µ¶· UZ"¸¹º»&¼½[¾¿ÀÁÂ&±BÃHR J1gadopentetate dimeglumine1(NMG)2[Gd(DTPA)]1B¯ÄRÅ
JÆ+ gadoterate meglumine1NMG[Gd(DOTA)]1B¯yl JÇ ±c!ÈBÉÊËUZB&RÌÃHR Jn± ÍÎÏ«À Gd(DTPA)2-\ gadodiamide,Gd(DTPA-BMA)"N
Gd(DOTA)-\yl« J gadoteridol, Gd(HP-DO3A)6-12
ÐÑÒÓÔ"ÀÕ(monomer)Ö×1ØÙtÚÛ(dimer)cK H (polymer) Ü Ö × 1 Vauthey = 13 [
[BO{Gd(DO3A)(H2O)}2
](2,11-dihydroxy-4,9-dioxa-1,12-bis[1,4,7,10-tetraaza-4,7,10-tris(carbox-ymethyl)cyclododecyl]dodecane-gadolinium(III)) Û (dimer)1Â)* Fig. 1 ÝÞ1F)*&ßÊàáGH(q = 2)12 âÛÅ J!ãäoÂåfg(rotation correlation time)jæ1ç  R1i!FÕ(monomer) 3.4 jèÛ(dimer) 4.61 dm3 mmol-1és-1
Fig. 1. Structural formula of [BO(DO3A)2].
Fig. 2. Structural formula of the ligand {pip(DO3A)2}6-.
Fig. 3. Structural formula of the ligand {bisoxa(DO3A)2}}6-.
Ç ¯ â Û Å J Ö × > ? B [pip{Gd(DO3A)(H2O)}2]N
[bisoxa{Gd(DO3A)(H2O)}2]1Â&[pip(DO3A)] = bis (1,4-(1-(carboxymethyl) -1,4,7,10-tetraaza-4,7,10-tris(carboxymeth-yl)-1-cyclododecyl-1,4-diazacycloh exane))1 {bisoxa(DO3A)2} = bis (1,4-(1-(carboxymethyl) -1-cyclo-dodecyl-1,
10-diaza-3, 6-dioxadecane))14ÂêëHÛ)* Figs. 2 N 3 ÝÞ1 ì í î 17
O-NMR5 EPR N NMRD(Nuclear Magnetic Relexation Dispersion)Ö×ÕNÛåfgNÂïðh1)ñäÞ1ÂÛ åfgãä@ÕBò1óÂâÛÅ JáGH ô GHõök÷@Õø1ùúó¯de÷,îûü1ýâÛÅ Jde÷(R1)@K +þÐ R.S. Ranganathan = 15A trimer5tetramer5hexamer N N N N N COO -OOC OOC N N N N COO -COO -OOC N N O O -N N N N COO -OOC OOC N N N N COO -COO -OOC N O O N H H O O -N N N N O -O -O O N N N N O -O -O O O O OH OH O -O O -O
octamerAKHMKHâ JÖ×1)ñ¦¯âÕ áGHú 1.01+de÷(R1)HMj+j ' ¡NUZfRNÂä ª÷¯+ JMÀÍÎÅ J&Ï[ RNR5\5a qR1"Na!"#RB$%ä ª÷1&&ÃH'ßKª(N)*êëGHB+1Fn!" KdeRdeRB¯,-.]R¥¦G9Hde/ Ê(0Ù Wh1¯]R JdeRÍLáNôdeR=ÊM1 1¯23ä4÷(imaging radiofrequency)1áde R1B"5ð h6háêëh(q)1ª((µeff)1]&&bG9Hg\g7 Ã(r)1Nfg(correlation time18c)1n6h!"9 R1 ∝ q(µeff)28c/r6 (1) fg:!B 'M;åfg(8r)1H<=de fg(8s)"NáG>õöfg(8m)1ù?M J@ H1+ÂAB 1/8c = 1/8r + 1/8s + 1/8m (2) 8c !CDHEF~\>fgòG1fg9Þ }HF~¯ëHI¡fgcìJ3åI¡KfgLû BêëhMy¤` Å JáG H(inner sphere water)\h D1Å JáGHhM'1GH&9H\de÷(relaxivity1R1)
My1+ôG H(outer sphere water)9Hde÷NO@P
²³ Gd ÃHQà,[HÂ 4f RS&FnTI(µeff)2 B
63BM2(BM=Bohr magneton)U¯&5±UVZ¡¯àá GH1Fn|%\W T1deRhiB 3.5 % 4.0mM-1s-11nhi@'X þYZ J²³cʳ[è æ \Ö×D\Ö¦2ªKHNÛ UZ"BST¿"ÂÕ JÖ×Â] ^_3Wh1"C DÛÅ J_3þ`¿Ö×ÛJRde÷(R1)1úab %@cd\K
2-1 ëe3(potentiometric titration) êëHNêëH ÃHÝÏÅ J\ëe3¡êfgNhi ðj pH (pH meter) Ü pH \ pH i$3Ek"lmen pH 7.0o0.05 N pH 4.0o 0.05 pt1ÃH(ionic strength)B I = 0.10 mol dm-3 Me4NNO3\S»&ÝoqêëHrßKs)êëH
¯?t\u/µv9H1e3EjwxM\·oÂ9Hjwy e3Z(0.1 mol dm-3 NaOH)f1gzrP(0.005 {|/()
2-2 9HWh(protonation constant) _3Wh(stability constant)} qêëH9HWhî FORTRAN ~ PKAS16Ò}1è
Å J_3Whî~ BEST16Ò} PKAS ~&1r
wqêëH\{h1ye3Z\(mol dm-3)1({|)1¿ cDêëH9HWh\àh1þ`wFëe3Ý|%h 1! 9HWh BEST ~&1Ýw\h ÍLqêëH { h1ye3Z\(mol dm-3)1({|)1"NqêëH\9H Wh1¿cDÅ J\_3Wh1þ`wëe3Ý|%h n¯ >~újwye3Zf1¯gÝK[9M-I (mass-balance)>~F¯Ý\IWhN±J9\1! }(jwyh\ pH i1n pHcalcd pHcalcd ëe3&$M\
pHi(pHobs) w7MP1fit (fit=(pHcalcd- pHobs)2)MP1ÝcD
Å J\_3WhMmþ`¿î SPE N SPEPLOT ~!q êëHNÅ J,~ pH iÝLÂJ±÷U
2-3 de÷(relaxivity)\$3 2-3-1 â(III)ÃH\$3
{â(gadolinium chloride)3.72 H 500 {|M&1"ÃHG 1¿è{' ¡Y EDTA¢2Na 4.6530 H 250 {| M&1"ÃHG¿è"n stock 1D\Bl3 â(III) ÃHo
M{â 10 {|1jw 0.5 mol dm-3 £·¤en(acetate buffer)oÂ
pHi 5.01nô¥j 2 eV¦jw 6 eʧ¨©(xylenol orange) ªÞZ1nf\«¬®¬" EDTA e31«¬F®¬q [¯¬f1b%e3°±1F EDTA ݲ³\!â(III) ÃH\ 2-3-2 qêëH\$3 ê´5±,~qêëH1ÂyµB 10 mmol dm-3¿î¶· ëe3 1|qêëH 2-3-3 Stock âÅ J(GdL)\ê´ {â(III)ÃHbqêëH" 1:1(hV)\V;¸ 1¹Wº qêëHYM 2%nf,jwen1¸ `j]» 10 ¼1¿½ ¾¿H 30 ¼1o»À1!|âÅ J 2-3-4 ,~ pH iâÅ Jê´ î,~\en âÅ J" 1:1(V)¸ 1!ê´,~ pH i â Å J 1 Ý o e n £ · (chloroacetic acid)/NaOH(pH 2-3)1£·/NaOH (pH 4-5)1PIPES/NaOH (pH 6-6.8)1ÁÂ
3TsC l p yri dine 3T sCl pyridin e CH3C H2ONa CH3CH2OH HO N H OH H2N N H NH2 HN N NH Ts Ts Ts O N O Ts Ts Ts HN N NH Ts Ts Ts N N N Ts Ts Ts 2Na N N N Ts Ts Ts 2Na + O N O Ts Ts Ts DMF N N N N Ts Ts Ts Ts N N N N H H H H H2SO4 1 00-1 20OC
/HCl (pH 9-10) pH iÃÄ¡o 0.1 mol dm-3\en 2-3-5 de÷\$3
ê´5±,~ pH i\ 6 ±,~(0.1 - 2.0 mmol dm-3)âÅ J
T1 (spin-lattice relaxation time) N T2 (spin-spin relaxation time)$31Bî
0.47 Tesla ÅÆ1$3E 900N 1800 Çn (pulse) r7Yp t1¥"»åÈÉ(inversion recovery)ÇnÊË$3âÅ J\ T11¿ ~fî Carr-Purcell-Meiboom-Gill ÇnÊË$3 T2i1í",~def gÌh(1/T1 N 1/T2)U1Ý|Í÷Bde÷ R1 R2
3-1. (ligand): DO3A scheme 1 DETA-3Ts DEA-3Ts TETA2Na+-3Ts cyclen-4Ts cyclen
NH NH HN HN NH NH N N COOH COOH N NH N N COOH COOH HOOC 2BrCH2COOtBu 2H2SO4 KOH BrCH2COOtBu KOH anion exchange N N HN N COOH HOOC HOOC CH3NHCH2COOH MeOH CH3NHCH2COOCH3 SOCl2 + CH3NHCH2COOCH3 NaOH MeOH N N N N COOH HOOC HOOC N O H CH3 AP-DO3A DODA DO3A Scheme 1
AP-DO3A scheme 2
Scheme 2
EN(DO3A)
2scheme 3
HOOC N H NH COOH SOCl2 MeOH N N HN N COOH HOOC HOOC + H3COOC N H NH COOCH3 MeOH K2CO3 N N N N COOH HOOC HOOC N N N N COOH HOOC COOH NH NH O O EN(DO3A)2 EDDME DO3A EDDME H3COOC N H NH COOCH3 Scheme 3 3-1-1 DETA-3Ts DO3A scheme 1 3-1-1 DETA-3Ts 16 (155 ) diethylenetriamine 20 pyridine , 50-60 88.9 466 ) TsCl 150 pyridine !" 2#$%, &'()*+ 20 #$, ',-*+), . 150 /012, 3 456789:;<=>? 74.3 , @A 84.68%, BC 171-173, 1H-NMR (200 MHz, CDCl3), D(ppm) 7.78-7.29 (m, 12H, ArH), 5.20 (t, 2H, ArNHCH2), 3.19-3.12 (m, 8H, NCH2CH2N), 2.43 (s, 9H, ArCH3) 3-1-2 DEA-3Ts 90.462 474 ) TsCl 480 diethyl ether, '()
16.02 153 ) diethanolamine 63 triethylamine !" 3 #$%, &'(),-*+ 20 #$, 5 CHCl3/H2O E, FGHIJ,
5 MeOH KLMN, :O=N? 28.35 , @A 33.3%, BC 92-94, 1H-NMR (200 MHz, CDCl3), D(ppm) 7.78-7.27 (m, 12H, ArH), 4.11 (t, 4H, NCH2CH2O), 3.38 (t, 4H, NCH2CH2O), 2.46 (s, 6H, OSO2ArCH3), 2.43 (s, 3H, NSO2ArCH3). 3-1-3 TETA 2Na+-3Ts
'PQ), 3.5 76 ) Na .O26R 120 , *+ 5 ST%: 1.5N6RU 120 , VW. 40.0 71 )DETA-3Ts O26R 300 , .XY!" 2 #$, Z[\(, ]^:_=>?, 5O26R89, :\@` 32 , @A 74.3%.
3-1-4 cyclen-4Ts
DEA-3Ts 28.0 49.4 ) 240 DMF , 32 52.55 ) TETA-3Ts-2Na 480 DMF , .XY 4 #$, ab\( , ',-*+) 200 /012, 5 95%6R89:\_=>? 25.35 , @A 70.8%, BC 50-60, 1H-NMR (200 MHz, CDCl3), D(ppm) 7.71-7.31 m, 16H, Ar-Hc, 3.43 (s, 16H, NCH2CH2Nc, 2.44 (s, 12H, Ar-CH3). 3-1-5 cyclen
cyclen-4Ts 20.5 . 70 98%H2SO4, 100-120).XY 48
#$%, 'de). 50%NaOH f pH \ 7.4, . 1 ghi, ' 80)* + 10 ST, jX34, IJ4k, 5lR89, IJ4k, :_=>? 6.45 , @A 65%, 1H-NMR (200 MHz, CDCl3), D(ppm) 3.00(s, 16H, NCH2CH2Nc,
13C-NMR (200 MHz, D
2O),D(ppm) 45.79(NCH2CH2Nc.
3-1-6 DODA
2g NaOH . 100ml MeOH m 10ml H2O,*+ 5 ST%, . 1.08g cyclen,
&*+ 30 ST, . 1.857ml tert-Butyl bromoacetate, 40-50)!" 48 #$, nopqIJ:;<=>?, 5O2rs89:_=>? 0.89g, @A 49%t 1H-NMR (200 MHz, D 2O), D(ppm) 3.10 (s, 4H, NCH2COOH), 2.70-2.53(16H, NCH2CH2N),13C-NMR(200 MHz, D2O), D (ppm) 182.99(COOH), 61.87 (CH2COOH), 55.10, 53.88, 47.85, 46.47 (NCH2CH2N). 3-1-7 DO3A :
1.5 NaOH . 100 MeOH m 10 H2O u. cyclen
sulfate(2u5.16 )u*+ 10 ST%uL. tert-Butyl bromoacetate(1.52 u10.32 )u!" 72 #$%uv 45-50°C u!" 20 #$%u wb\(u L. 0.8 NaOHu*+ 10 ST%u L. tert-Butyl
bromoacetate(0.76u5.16 )u!" 72 #$%uv 45-50°C u! " 20 #$%uIJ:_=>?.2xu5y2fv pH 11 5zu{|01 }~u5lu 0.02N lkIJ%:;<=>? 0.51 u @A 25.96%t13C-NMR(200MHz, D2O), δ(ppm) 177.43, 172.35(NCH2COOH), 58.32, 56.02(NCH2COOH), 54.72, 51.99, 50.63, 45.20 (NCH2CH2N)t 3-1-8 CH3NHCH2COOCH3:
(CH3NHCH2COOH)(10g , 112.24mmole). 200ml MeOH ,
'de)*+,PQ,L SOCl2 (16.28ml, 224.49mmole)u!" 20
#$%IJu:;=>? 11.23gu@A 97.06%t 1H- NMR(D2O), D(ppm): 2.72 (CH3NH-) , 3.77 (-COOCH3) , 3.94 (-NHCH2COOCH3)t
3-1-9 AP-DO3A:
DO3A-4HCl(2g , 4.097mmole). 100ml MeOH u NaOH pH fv 11.59 u.X*+v\ 40 ~ 50$uL3 CH3NHCH2-COOCH3 (0.55g , 5.33mmole)u!" 48 #$%uIJ: <=>?.2xu5y2f pH v 11 5z,{|01}~u5l 9, 0.035N l9kuIJ%:;<=>? 0.61 u@A 35.67 %t13C- NMR(200MHz,D2O), D(ppm): 180.61,173.21 (NCH2COOH), 170.9
(NCOCH2NHCH3), 52.88 (NCOCH2NHCH3), 58.83,58.53, (NCH2COOH), 54.48,52.33,51.43,45.54 (NCH2CH2N), 46.24 (NCOCH2NHCH3)t
3-1-10 EDDME:
EDDA(5g , 28.41mmole). 150ml MeOH ,.X*+v\ 40 ~ 50uL SOCl2 (8.24ml, 113.64mmole)u!" 20 #$%IJu
:_=>? 4.76gu@A 82.21%t 1H- NMR(D2O) , D(ppm): 3.48 (NCH2CH2N) , 3.75 (NCH2COOCH3) , 4.03 (NCH2COOCH3)t
3-1-11 EN(DO3A)2?:
DO3A(0.5g , 1.37 mmole). 50ml MeOH u pH fv 11.59 u.X*+v\ 40 ~ 50$uL3 EDDME(0.182g ,
0.892mmole)u!" 48 #$%IJu:<=>?.2xu5 y2f pH v 11 5zu{|01}~u5l9u 0.035N l 9kuIJ%:;<=>? 0.26 u@A 43.33 %t
3-1-12 EN(DO3A)2`:
EN(DO3A)2 (0.19g , 0.228mmole) 20ml 2uL.(0.083g , 0.228 mmole) Gd2O3,.Xv 90 ~ 100Y!"u!" 24 #$%u34
/3 Gd2O3uL4kIJ:<=>? 0.15gu@A 57.69%t
3-2 X-
3-2-1 1 ¡¢£
Table 1 Protonation Constants for AP-DO3A, DOTA, DO3A, and HP-DO3A at I = 0.10 mol dm-3 (CH3)4NCl and 25 ± 0.1°C. Uncertainty (¤) in log KnH values are given in parentheses.
Equilibrium AP-DO3A DOTAa DO3Aa HP-DO3Aa [HL]/[ L][ H] 11.19(4) 11.73(3) 11.59(3) 11.96(2) [H2L]/[HL] [H] 9.38(2) 9.40(2) 9.24(3) 9.43(1) [H3L]/[H2L][H ] 4.58(3) 4.50(3) 4.43(8) 4.30(1) [H4L]/[H3L][H ] 3.73(3) 4.19(1) 3.48(8) 3.26(2) pKa 28.88 29.82 28.74 28.95 a. Data were obtained from ref.17.
Table 1 AP-DO3A DOTA!DO3A " HP-DO3A#$%AP-DO3A & DOTA!DO3A " HP-DO3A '()*+ #,-. /012345678 9:(electrostatic repulsion);<=
>?@A-B(basicity)&CDA-EF@A-/G/ H IJ(ionized acetate group)KB&%67LM(electrostatic effect)NOP2 cyclen G/IJQR & 10.6 NO S 11.4-11.7 .%T DOTA R C DO3A .%1%2 7UVW(charge effect)FXYZ[7U DOTA G\X]7 ^ ( KR &C_XD[7U DO3A " AP-DO3A EAP-DO3A R ()`Yabc(amide)-/a bcd7 Ce%B&C DO3A fgHP-DO3A hEi DO3A " AP-DO3A 'XYD[7UjR kl DOTA fm 01%2 HP-DO3A R ()`Yn7 oJpqJrsJ-. /<=-/pBNO;t u,R@ ?R ;\p67LM,R@ vwx%R@ yz1\Sf{*+ /67:|} LM;t67:|}~f{P^( p-/X[7 J~f{^(R -. ; DOTA! DO3A!HP-DO3A AP-DO3A R@ TRD" RZ &() -. /pJ. /% Ip (logK = 4.6)G 3-2-2 :p M7Y@~p ¡1¢ £G7¤H ¥ 1 1¡¦§l¢¨©ª« 0.005¬p NaOH f¨®¯;p°M BEST ±² Pp³M)g pH K´µz Y 25%¶H¡2¢¥ -¥ ·¸¡ligand-ligand competition titration¢1H !¥ " EDTA 1 1 1¡¦§l¢¨ ) pH ¹º»¯ª¼½¾¿ 10-15 +ÀÁp|};° M BEST ±²Pp³M)g pH(pH = 2 K) 25%¶HÂÃÄpÅ2Æ) pH = 2
ÇÈÉ&iYÊ¥ Ë=%Åp´µ ~ AP-DO3A Zn2+!Ca2+" Cu2+ÌH Ë=pM £G7j1 Gd3+ AP-DO3A ;Ë= CmÍÅH ) pH Ì 2 KÈÉ&iYÊ¥ Ë= ÎP¶HÏ+l 25%ÅpÐ £G7K´µM¥ -¥ ·¸f
Table 2 Stability constants of Gd3+, Zn2+, Ca2+ and Cu2+ complexes with AP-DO3A, DOTA, DO3A, and HP-DO3A at I = 0.10 mol dm-3 (CH3)4NCl and 25.0 ± 0.1°C.
Uncertainty (σ) in log K values are given in parentheses.
log K
` parameter AP-DO3A DOTAa DO3Aa HP-DO3Aa
[GdL]/[Gd][L] 21.54 25.30 21.00 23.80 log KGdL' (pH 7.4) 16.76 18.33 14.97 17.21 [CaL]/[Ca][L] 14.19 17.23 11.74 14.83 log KCa L' (pH 7.4) 6.19 10.26 5.71 8.24 [ZnL]/[Zn][L] 19.47 21.05 19.26 19.37 log KZnL' (pH 7.4) 13.70 14.08 13.23 12.78 [CuL]/[Cu][L] 20.68 22.63 22.87 22.84 log KCuL' (pH 7.4) 15.91 15.66 16.84 16.25
a. Data were obtained from ref.17.
M BEST ±²;p:Ñ Table 2 ;Ò AP-DO3A Gd3+!Ca2+!Zn2+" Cu2+ÌH ;Ë=pÓ Ô + Õ 2 [Gd(AP-DO3A)] (21.54) > [Cu(AP-DO3A)]
(20.68) > [Zn(AP-DO3A)](19.47) > [Ca(AP-DO3A)](12.01) Table 2 Gd3+!Zn2+!Ca2+ " Cu2+H , AP-DO3A!DOTA!DO3A " HP-DO3A ÌYÊ¥ p
ÓÔ2Å >Ö > × > Øyz.%1iH 7UÙB(charge density)Y ÚÛlC#$p:[Ca(DOTA)]2
> [Ca(HP-DO3A)]> [Ca(AP-DO3A)]≈ [Ca(DO3A)]<=ÜÔpyz.%1 %2ØH *+ KÝmÞߥ;$ߥ DOTA " HP-DO3A Øp&C$ॠAP-DO3A " DO3A f m#$¥Í`YCmBpYÊ¥ Øpám $âߥÅH $ߥ DOTA " HP-DO3A ;Ë=p :&m AP-DO3A " DO3A ;Ë=p 3-2-2 ãäp
z3¶)(å»pãäl: C2æzãä1ç)(å»(â(pH =
7.4) ãäèp H YÊ¥ Ë=péW~±²è²êÒp M + ë Më (3) M H L YÊ¥ ML ãäpì1ç$pHãäèpìѲ(4) [ML] Kcond = { [L] + [HL] + [H2L] + ííí }-1 (4) [M] ãä :pÚîѲ (5) [L] Kcond = Ktherm (5) [LT] LT (éWpYÊ¥ ïðBñѲ (6) ;Ò LT = { [L] + [HL] + [H2L] + ííí } (6) ²(6) sò²(5) ó Kcond = Ktherm{1 + K1H[H+] + K1HK2H[H+]2 +ííí}-1 = KthermαH (7) αH= {1 + K1H[H+] + K1HK2H[H+]2 + ííí}-1 [Gd(AP-DO3A)])$ pH èpã䲡7¢ Ñ Table 2 ;Ò)(å»(â¡pH = 7.4¢ãäèp ÓÔ2 [Gd(DOTA)] > [Gd(HP-DO3A)] > [Gd(AP-DO3A)] > [Gd(DO3A)]+Õ2 18.33!17.21!16.76 " 14.97 3-2-3. ôõp ö÷<v,løpùyzf{,lø¶HK^(úHpGd3+H .%1(å»pH ÑZn2+!Ca2+"Cu2+ Gd3+ (ûüéWtÁGd3+H úHýf (å»p¥ Ñb J!þÌË=<=(â|} (å»Zn2+!Ca2+iCu2+ÌH Zn2+1<=Å )延HÝ%.%1Zn2+)(plasma)pðB 10 ~ 50 µmol dm-3Ñ YÊ¥ Ë=prséW ýCpÅ H Cu2+hE YÊ¥ Ë=pjCu2+)
ðBY 1 ~ 10 µmol dm-3;ÐrsýCÅH Ca2+)
ðBhEmÞ2.5 ~ 4 mmol dm-3j1Ca2+ PY-DTPA!HP-DTPA!DTPA
"DTPA-BMA;Ë=pCg%ÐÅH 0ÅrsýÛ(å»CpH ÑFe3+
& Å(rséWó
YÊ¥ ÅH c" (å»ðBCmpH ÑZn2+!Ca2+Cu2+Kppôõ(selectivity
constant)Plog K (Gd3+
/Mn+)( Mn+ =Zn2+!Ca2+"Cu2+) Table 3 Selectivity constants of [Gd(AP-DO3A)]-, [Gd(DOTA)]-, [Gd(DO3A)] and [Gd(HP-DO3A)] vs Zn2+, Ca2+and Cu2+. Parameter AP-DO3A DOTAa DO3Aa HP-DO3Aa log K(Gd/Zn) 3.07 4.25 1.74 4.43 log K(Gd/Cu) 0.86 2.67 -1.87 0.96 log K(Gd/Ca) 7.35 8.07 9.26 8.98 log K sel' 5.32 6.95 4.12 6.95
a. Data were obtained from ref.17.
Table 3 ý [Gd(AP-DO3A)], [Gd(DOTA)]-, [Gd(DO3A)] " [Gd(HP-DO3A)]- Zn2+!Ca2+i Cu2+ÌH ¾pôõ[Gd(DO3A)] , Zn2+pôõ2 1.74ôõCgxT, Cu2+ôõSÞ[
0 !"[Gd(DO3A)]SÞ#å$%&i Cu2+ûüÁ Gd3+úHýf<=
'ù%[Gd(DO3A)]³Mö÷<vp,lø/AP-DO3A hEi DO3A $à¥pYÊ¥ EÅ Ø!×"ÖÌ H pôõ( [Gd(HP-DO3A)])*Òý AP-DO3A YÊ¥ DO3A ',ÅH YC+pôõ 3-3 ,-.pÃÄ Üö(paramagnetic)p,-.yz@È+;/0P »1(inner-sphere) Û1(outer-sphere),-.ÂÃÄ;pYÊ¥ hE ¥$j12`Y#)3JÍ(Y»14+ 5);,-./0yz1f{»1,-.6;<=Û1,-/0781 #) )97ö:.(radio frequency)i;Bèvw»1,-.p% è²êÒp R1 ∝ q(µeff)2τc/r6 (8) q2»14+ µeff2H YVö<τc2)9ö=èÜ öp#ÚK¾(correlation time)r2H T»14+ p > H u,Å?µeff2 0.94 µBr)Gd(III)-OH2?@Gd-O
pcA22.50+0.04B,`Y#)3JpYÊ¥ Å ?µeff"rW2;qiτc=2CÂDE;pÅp
,-.yz%
0 2 4 6 8 10 12 14 0 2 4 6 8 10 R1 (mM -1 s -1 )
rotation timeτr)(2) 7 {H,-K¾(electron spin relaxation timeτs)(3) 4
+ ûü&.(water exchange rateτM)Úî²²¡9¢;Ò
τc-1 = τr-1 + τs-1 + τM-1 (9) ,È++ Å?4+ ûü&. 7 {H,-p&.IC+ FGfJ;_Y4+ ûü&. 7 {H,-&.& vw#ÚK¾K+ Å^(LR1M&NO.% Y@ (1) ;pLcCÅH (2) ;pL)®¯ + FG&.C4+ ûü&."7 {H,-&.JK_Y+ FG&vw#ÚK¾P#ÚK¾NO;R1/ )$pHè[Gd(AP-DO3A)]p,-.R1,pHLN ÑFig. 4;Ò[Gd(AP-DO3A)])pH4.0KR1P OP(R1 ≈ 6.0 mM-1s-1)(T = 37 Q, 20 MHz)E)pH4.0KÅ R1&RpHSgNO.%2)pHKJ/ . & T t Ð iÅ H Ë =¥ Á c [Gd(AP-DO3A)]pÅH /»14+ NO óR1Cm [Gd(AP-DO3A)])pH2.2KpR1mÞ11.80 UV_YÅH ®¯p R1¡11.90¢#W)pHKAP-DO3AYÊ¥ XY ÅH cÛKAP-DO3ApZå[Gd(EN(DO3A)2)][,-., -.mÞ7.2 mM-1 s-1(T = 37 Q, 20 MHz) pH
Fig 4. pH dependence of the relaxivity for the [Gd(AP-DO3A)],all in 0.1mol.dm-3 buffers at 20MHz and 37.0 \ 0.1Q
3-4.
Â]^_yz1=ý AP-DO3A " EN(DO3A)2`aZå¥
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ÅH him,-.
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