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 =

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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+

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& 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%

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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/@

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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.

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

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4468-4473.

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數據

Fig. 1. Structural formula of [BO(DO3A) 2 ].
Fig. 1. Structural formula of [BO(DO3A) 2 ]. p.2
Fig. 2. Structural formula of the ligand {pip(DO3A) 2 } 6- .
Fig. 2. Structural formula of the ligand {pip(DO3A) 2 } 6- . p.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

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 p.11
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

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 p.14

參考文獻

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