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高分子金屬配位化合物之磁振造影劑

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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&9H

UZBL,[ H\]RJ9,!^_`a spin-lattice(T1) b/c(T2)defg\hi"jkG9HRlm&de 2-51Fn!" opqrsNtWrsg\uvwxqyzg{|U}G9 Hde0,~1U!B€y1~f0 T1N T2a HM]R‚ƒ„…J"N2†‡0 T2ˆ]RJ9‰Š‹Œ n€UZ>Ž‘y\wx’aHM‚ƒ„… J+“1de”• ‚ƒ„…JN–GH—˜™1tš ”•›uvœžjNŸš”•›uvœ` ¡!¢#Y% £+ˆ]RJ9¤¥¦§¨©\q‹+` ª T21n«¬­®¤ #Y%Ÿš”• aHM]R‚ƒ„…J¯&1°±²³ Gd ´µ¶·„… UZ"¸¹º»&¼½[¾¿ÀÁÂ&€±BÃHR‹… J1‰gadopentetate dimeglumine1(NMG)2[Gd(DTPA)]1B¯ÄRŅ

JÆ+ gadoterate meglumine1NMG[Gd(DOTA)]1B¯yl„…JǏ €±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)*&ߏÊàáGH(q = 2)12 âÛŅJ!ãäoÂå˜fg(rotation correlation time)žj€æ1ç  R1i!FÕ(monomer) 3.4 žjèÛ(dimer) 4.61 dm3 mmol-1és-1

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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×ÕNÛ嘐™fgNÂïðh1)ñäÞ1ÂÛ 嘐™fgãä@ÕBò1óÂâÛŅJáGH 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

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octamerAKHMKH₃„…JÖ×1)ñ¦¯â‚ƒÕ áGHú 1.01+de÷(R1)HMžj+žj  ' ¡NUZfRNÂä ª÷¯+“„…JMÀÍÎŅJ&Ï[ RNR5\5a˜ q‹R1"Na!"#RB$%ä ª÷1&&‚ƒÃH'ßKª(N)*êëGHB+1Fn!" KdeRdeRB¯,-.]R¥¦G9Hde/ Ê(0Ù Wh1¯]R„…JdeRÍLáNôdeR=ÊM1 1¯23ä4÷(imaging radiofrequency)­1áde R1B"­5ð h6háêëh(q)1ª((µeff)1]&&bG9Hg\g7 Ã(r)1Nfg(correlation time18c)1n6h!"­Ž9 R1 ∝ q(µeff)28c/r6 (1) fg:!B 'M;‰å˜fg(8r)1 H<=de fg(8s)"NáG>õöfg(8m)1ù?M ‚ƒ„…J˜@ H—˜™1+A™B‰­ 1/8c = 1/8r + 1/8s + 1/8m (2) 8c !CDHEF~\>šfgòG1™fg›9Þ }HF~¯ëHI¡fgcìJ3—˜‰å˜I¡KfgLû BêëhMy¤` ‚ƒÅ…JáG…H(inner sphere water)\h D1‚ƒÅ…JáGHhM'1GH&9H\de÷(relaxivity1R1)

My1+ôG…H(outer sphere water)9Hde÷NO@P

²³ Gd ÃHQà,[ H 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‚ƒ„…J‰²³Šcʳ[‡è €æ \Ö׆‡D\Ö¦2ªKHNÛ‚ƒ„… UZ"BST¿"ÂÕ‹…JÖ×Â] ^_3Wh1"C DÛ‚ƒÅ…J_3þ`¿Ö×ÛJRde÷(R1)1úab %@cd\K



2-1 ëe3(potentiometric titration) êëHNêëH ‚ƒÃHÝÏ‚ƒÅ…J\ ëe3¡êfgNhi ð j pH (pH meter) ­•Ü pH \ pH i$3Ek"lmen  pH 7.0o0.05 N pH 4.0o 0.05 pt1ÃHœ(ionic strength)B I = 0.10 mol dm-3  Me4NNO3\S»&ÝoqêëHrߏKs)êëH

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¯?t‡\u/µv9H‹1e3EjwxM\·oÂ9H‹jwy e3Z(0.1 mol dm-3 NaOH)f1gzr‡P(0.005 {|/()

2-2 9H‹Wh(protonation constant) _3Wh(stability constant)} qêëH9H‹Whî FORTRAN ~Ž PKAS16Ò}1肃

ŅJ_3Whî ~Ž BEST16Ò} PKAS ~Ž&1r

wqêëH\{€h1ye3Z\‚(mol dm-3)1ƒ„({|)1¿ cDêëH9H‹Wh\àh1þ`wF ëe3Ý|%h…1›!†‡ 9H‹Wh BEST ~Ž&1Ýw\h…ÍLqêëH ‚ƒ{€ h1ye3Z\‚(mol dm-3)1ƒ„({|)1"NqêëH\9H‹ Wh1¿cD‚ƒÅ…J\_3Wh1þ`w ëe3Ý|%h…n¯ >~Žúˆ‰‘jwye3Zf1¯ŠgݏK[‹9M-IŒ (mass-balance)>~ŽF¯ŽÝ\IŒWhN±J9\‚1! }‡(jwy„h\ pH i1n› pHcalcd‘ pHcalcd ëe3&$M\

pHi(pHobs) w7MP1‘›’fit (’fit=“(pHcalcd- pHobs)2)MP1›ÝcD‚

ƒÅ…J\_3WhMm”þ`¿î SPE N SPEPLOT ~Ž!•‡q êëHN‚ƒÅ…J,~ pH i­ÝLÂJ±‚–÷U

2-3 de÷(relaxivity)\$3 2-3-1 â(III)‚ƒÃH‚\$3

—{˜‹â(gadolinium chloride)3.72 ™H 500 {|Mš&1"›ÃHG 1¿œèžŸ”—{' ¡Y EDTA¢2Na 4.6530 ™H 250 {| Mš&1"›ÃHG¿œèž"n‘ stock 1D\Bl3 â(III) ‚ƒÃH‚o

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 [¯¬f1›b%e3°±1F EDTA ݲ³\„›!†‡â(III)‚ƒ ÃH\‚ 2-3-2 qêëH‚\$3 ê´5±,~qêëH1‚yµB 10 mmol dm-3¿î¶· ëe3 1†|qêëH‚ 2-3-3 Stock ₃ŅJ(GdL)\ê´ {â(III)‚ƒÃHbqêëH" 1:1(€hV)\V;¸…1¹Wº qêëHYM 2%nf,jwen1¸…`j]» 10 ¼1¿½ ¾­¿H 30 ¼1o»À1›!|₃ŅJ 2-3-4 ,~ pH i₃ŅJê´ î,~\en ₃ŅJ" 1:1(„V)¸…1›!ê´,~ pH i  ⠂ ƒ Å … J   1 Ý o   e n  ‰ ­  ˜ £ · (chloroacetic acid)/NaOH(pH 2-3)1£·/NaOH (pH 4-5)1PIPES/NaOH (pH 6-6.8)1ÁŒ‹Â

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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)₃ŅJ

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$3₃ŅJ\ 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

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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)

2

 scheme 3 

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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, '()

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 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(2 u5.16 )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

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bromoacetate(0.76 u5.16 )u!" 72 #$%uv 45-50°C u! " 20 #$%uIJ:_=>?.2xu5y2fv pH 11 5zu{|01 }~€u5l‚ƒu„… 0.02N l‚ƒkIJ%:;<=>? 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†‡:

ˆ‰(CH3NHCH2COOH)(10g , 112.24mmole). 200ml  MeOH ,

'de)*+,ŠPQ,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 uŒ NaOH  pH Žfv 11.59 u.X*+v\‘ 40 ~ 50$uL3’ CH3NHCH2-COOCH3 (0.55g , 5.33mmole)u!" 48 #$%uIJ: “<=>?.2xu5y2f pH Žv 11 5z,{|01}~€u5l ”9,„… 0.035N l”9kuIJ%:;<=>? 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 uŒ pH Žfv 11.59 u.X*+v\‘ 40 ~ 50$uL3’ EDDME(0.182g ,

0.892mmole)u!" 48 #$%IJu:“<=>?.2xu5 y2f pH Žv 11 5zu{|01}~€u5l”9u„… 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 ~ 100™šY!"u!" 24 #$%u34›

/3’ Gd2O3uL4kIJ:<=>? 0.15gu@A 57.69%t

3-2 X-œž

3-2-1 Ÿ1 ¡ž¢£

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.

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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 -. ;ƒ„… DOTA! DO3A!HP-DO3A † AP-DO3A R@ ‡ˆ„TRD" RZ &()‰ -. /pJŠ. /‹%  Ip (logK = 4.6)GŒ 3-2-2 :Žp‘’ “ ”M7•–—Y@˜~—ƒ™š›œžŸp ¡1¢ £G7•–—¤€›œH ¥• ƒ 1 1¡¦§l¢¨ž©ƒª« 0.005¬­p NaOH f–¨ž®¯€;™šp–°”M BEST ±² P™š›œžŸp—³M›œžŸ)g pH K´µz Y 25%¶H¡2¢¥• -¥• ·¸–—¡ligand-ligand competition titration¢—1›œH !¥• " EDTA ƒ 1 1 1¡¦§l¢¨ž )– pH ¹º»–¯ª¼½¾¿ 10-15 +ÀÁp|};š–° ”M BEST ±²P™š›œžŸp—³M›œžŸ)g pH(pH = 2 K) 25%¶HƒÂÃÄpśœžŸ2Æ) pH = 2

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njÈÉ&iYÊ¥• Ë=žŸ%śœžŸp´µƒ ~—™š AP-DO3A Zn2+!Ca2+" Cu2+̛œH Ë=žŸp”M £G7•–—™šj1 Gd3+ AP-DO3A ;Ë=›œžŸ CmÍśœH ) pH Ì 2 KÈÉ&iYÊ¥• Ë=ž ŸÎP›œžŸ¶HÏ+l 25%śœžŸpЗƒ £G7•–—™šK´µ”M¥• -¥• ·¸–—f™š 

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;™šp:ŽÑ Table 2 ;Ò AP-DO3A Gd3+!Ca2+!Zn2+" Cu2+̛œH ;Ë=žŸpÓ 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+›œH , AP-DO3A!DOTA!DO3A " HP-DO3A ÌYÊ¥• p

›œžŸÓÔ2śœžŸ >֛œžŸ > כœ žŸ > ؛œžŸyz.%1i›œH 7UÙB(charge density)Y Ú‚ÛlC#$›œžŸp:Ž[Ca(DOTA)]2

> [Ca(HP-DO3A)]> [Ca(AP-DO3A)]≈ [Ca(DO3A)]<=ÜÔpyz.%‹1 %2؛œH *+ žKÝmÞߥ•;ƒ$œß¥• DOTA " HP-DO3A  Øžp&C$œà¥• AP-DO3A " DO3A f m#$¥•Í`YCmBpYÊ¥• Øžpám $âߥ•śœH $œß¥• DOTA " HP-DO3A ;Ë=p›œ žŸ:Ž&m AP-DO3A " DO3A ;Ë=p›œžŸ 3-2-2 ã䏐p‘’

z3¶›œžŸ)(Ÿå»pã䏐l:Ž C2æzã䏐1盜žŸ)(Ÿå»(â(pH =

(12)

7.4) ãäèp ›œH YÊ¥• Ë=›œžŸpéW~±²è²êÒp  M + ë Më (3) M ›œH L YÊ¥• ML ›œžŸ ã䏐pì1ç„$pHãäèpìѲ(4)  [ML] Kcond = { [L] + [HL] + [H2L] + ííí }-1 (4) [M] ã䏐 :ŽpÚîѲ (5)  [L] Kcond = Ktherm (5) [LT] LT ‰(žéWpYÊ¥• ïðBñѲ (6) ;Ò  LT = { [L] + [HL] + [H2L] + ííí } (6) €²(6) sò²(5) ó Kcond = Ktherm{1 + K1H[H+] + K1HK2H[H+]2 +ííí}-1 = KthermαH (7) αH= {1 + K1H[H+] + K1HK2H[H+]2 + ííí}-1 [Gd(AP-DO3A)]›œžŸ)„$ pH èpã䏐²¡7¢ ™šÑ Table 2 ;Ò)(Ÿå»(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+›œH .%1(Ÿå»p›œH ÑZn2+!Ca2+"Cu2+ Gd3+›œžŸ (›œûüéWtÁGd3+›œH úHýf (Ÿå»p¥• Ñb J!þ†ÌË=žŸ<=(â„|} (Ÿå»Zn2+!Ca2+iCu2+̛œH ƒZn2+1<=śœžŸ )延HÝ%.%1Zn2+)(plasma)pðB  10 ~ 50 µmol dm-3Ñ YÊ¥• Ë=pžŸ rséW ýCpÅ ›œH Cu2+hE YÊ¥• Ë=p›œžŸjCu2+)

ðBY 1 ~ 10 µmol dm-3;ƒÐ—rsýCśœH Ca2+)

ðBhEmÞ2.5 ~ 4 mmol dm-3j1Ca2+ PY-DTPA!HP-DTPA!DTPA

"DTPA-BMA;Ë=p›œžŸCg%З€Å›œH  0śœžŸrsý‚Û(Ÿå»Cp›œH ÑFe3+

(13)

& śœžŸ(rséWó„ƒ

YÊ¥• śœH cƒ" (Ÿå»ðBCmp›œH ÑZn2+!Ca2+†Cu2+žKppôõ(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+̛œH 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 $œà¥•pYÊ¥• EśœžŸ Ø!×"ÖÌ ›œH pôõ( [Gd(HP-DO3A)]Œ)*Òý AP-DO3A YÊ¥• DO3A ',śœH YC+pôõ 3-3 ,-.pÃÄ Üö(paramagnetic)›œžŸp,-.yz@ È+;/0P »1(inner-sphere) Û1(outer-sphere),-.ÂÃÄ;‘’pYÊ¥• hE ¥•„$j12`Y#)3JÍ(Y»14ž+ 5);ƒ,-./0yz1f{»1,-.6‡;<=Û1,-/0ƒ781 #) )97ö:.(radio frequency)i;Bèvw»1,-.p% è²êÒp  R1 ∝ q(µeff)2τc/r6 (8) q2»14ž+ µeff2›œH YVö<τc2)9ö=èÜ öŸ p#ÚK¾(correlation time)r2›œH T»14+ p > H u,śœžŸ?µeff2 0.94 µBr)Gd(III)-OH2?@Gd-O

pcA22.50+0.04B,`Y#)3JpYÊ¥• śœžŸ ?µeff"rW2;ƒqiτc=2CÂDE;‘’pśœžŸp

,-.yz%

(14)

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++ śœžŸ?4+ ûü&. 7 {H,-p&.IC+ FGfšJ;ƒ_Y4+ ûü&. 7 {H,-&.& vw#ÚK¾K+ śœžŸ^(LžR1M&NO.% Y@ (1) ;špLžŸƒcCśœH (2) ;špLžŸ)®¯ + FG&.‡šC4+ ûü&."7 {H,-&.JK_Y+ FG&vw#ÚK¾P#ÚK¾NO;ƒR1/­ )„$pHè[Gd(AP-DO3A)]›œžŸp,-.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 ›œžŸR1&RpHSgNO.%2)pHKJ/ Š . & T  ƒ t Ð — iÅ › œ H Ë =¥ • Á š c   [Gd(AP-DO3A)]pśœH /»14+ NO óR1Cm  [Gd(AP-DO3A)])pH2.2KpR1mÞ11.80 UV_YśœH ®¯p R1¡11.90¢#ŒW)pHKAP-DO3AYÊ¥• XY‰ śœH c‚ÛKƒAP-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]^_yz1ž=ý AP-DO3A " EN(DO3A)2ˆ`aZ奕

@ śœH ž NO,-.):ŽbÃÄ/З ƒZå£G ÃÄ%PƒZåpUå AP-DO3A f : ŽbÃč:Žbcý[Gd(AP-DO3A)] Ø!×"֛œ H ôõ [Gd(HP-DO3A)]Œ)),-.ÃÄ/[Gd(AP-DO3A)] ,-.2 6.0 mM-1 s-1Zå[Gd(EN(DO3A)2)],-.kmÞ 7.2 mM-1s-1 def`#gž0êÒ YÊ¥• KG/@

(15)

śœH him,-.



1. Stark, D.D.; Bradley, W.G., Jr. eds. Magnetic Resonance Imaging, 2nd Ed., St Louis, MO: CV Mosby; 1991.

2. Lauffer, R.B. Chem. Rev., 1987, 87,901-927.

3. Tweedle, M.F. In Bunzli, J.C.-G., Choppin, G.R., eds. Lanthanides Probes in Life, Chemical, and Earth Science. New York, N.Y.: Elsevier; 1990: 127-179. 4. Watson, A.D.; Rocklage, S.M.; Carvlin, M.J. Contrast Media. In Stark, D.D.;

Bradley, W.G., Jr. eds. Magnetic Resonance Imaging, 2nd Ed., St Louis, MO: CV Mosby; 1991.

5. Chang, C.A. Eur. J. Solid State Inorg. Chem. 1991: 28, 237-244. 6. Tweedle, M.F. Invest. Radiol. 1992: 27, S2-S6.

7. Chang, C.A. Invest. Radiol. 1993: 28, S21-S27.

8. Chang, C.A.; Ochaya, V.O. Inorg. Chem., 1986,25,355-358.

9. Carvalho, J.F.; Kim, S. H.; Chang, C.A. Inorg. Chem., 1992, 31, 4065-4068 10. Kumar, K.; Chang, C.A.; Tweedle, M.F. Inorg. Chem., 1993, 32, 587-593. 11. Chang, C.A.; Brittain, H.G.; Telser, J.; Tweedle, M.F. Inorg. Chem., 1990, 29,

4468-4473.

12. Kumar, K.; Sukumaran, K.V.; Tweedle, M.F. Anal. Chem., 1994, 66, 295 13. Toth, E.; Vauthey, S.; Pubanz, D.; Merbach, A. E. Inorg. Chem., 1996, 35,

3375.

14. Powell, D. H.; Dhubhghaill, O. M. N.; Pubanz, D.; Helm, L.; Lebedev, Y. S.; Schlaepfer, W.; Merbach, A. J. Am. Chem. Soc., 1996, 118, 9333.

15. Ranganathan, R. S. etal, Invest Radiol. 33,779-797, 1998.

16. Martell, A. E. and Motekaitis, R. J. Determination and Use of Stability Constants, 2nd edn., VCH, New York, 1992.

17. Kumar, K., Chang, C. A., Francesconi, L. C., Dischino, D. D., Malley, M. F., Gougoutas, J. Z., Tweedle, M.F. Inorg. Chem., 1994, 33, 3567.

數據

Fig. 1. Structural formula of [BO(DO3A) 2 ].
Table 2 Stability constants of Gd 3+ , Zn 2+ , Ca 2+  and Cu 2+  complexes with AP-DO3A,  DOTA, DO3A, and HP-DO3A at  I = 0.10 mol dm -3  (CH 3 ) 4 NCl and 25.0  ± 0.1°C
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

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