The effect of a phosphodiester linking group on albumin binding, blood half-life, and relaxivity of intravascular diethylenetriaminepentaacetato aquo gadolinium(III) MRI contrast agents.
Amphiphilic gadolinium complexes were investigated as potential magnetic resonance imaging (MRI) contrast agents. A series of complexes was synthesized in order to study the effect of hydrophilic phosphodiester groups on albumin binding, relaxivity, and blood half-life in rats. Thus, compound 11a, a diethylenetriaminepentaacetato aquo gadolinium(III) (Gd-DTPA) derivative with an octyl substituent, was synthesized and compared to 5b, the analogous octyl derivative containing a phosphodiester linkage between the gadolinium chelate and the alkyl chain. Likewise, 11b, a naphthyl Gd-DTPA derivative, was compared to the naphthyl phosphodiester derivative 5c. A direct comparison is not available for 5a, a 4,4-diphenylcyclohexyl phosphodiester Gd-DTPA derivative; however, its pharmacokinetic properties mirror those of the other phosphodiester derivatives. Although the introduction of the phosphodiester moiety decreased log P by approximately 1.7 units, albumin binding data obtained in 4.5% human serum albumin (HSA) indicated that derivatives containing the phosphodiester group exhibited somewhat higher albumin affinity than their alkyl analogues (54 +/- 5 and 44 +/- 4% for 5b and 11a, respectively; 40 +/- 4 and 30 +/- 3% for 5c and 11b, respectively). Both classes of agents were characterized by enhanced relaxivity in the presence of 4.5% HSA (r1 = 16-42 mM(-1) s(-1) at 20 MHz and 37 degrees C) as compared with the relaxivity values measured in phosphate-buffered saline (PBS) alone (r1 = 4.6-6.6 mM(-1) s(-1) at 20 MHz and 37 degrees C). Pharmacokinetic data indicated that compound 5b had a half-life of 14.3 +/- 1.8 min in the rat as compared with a half-life of 6.20 +/- 0.04 min for the non-phosphodiester analogue 11a. Similarly, the half-life obtained for the phosphodiester 5c was 14.3 +/- 1.7 min as compared with a half-life of 6.80 +/- 0.03 min for 11b. The percent biliary excretion was significantly lower for the phosphodiester compounds than for non-phosphodiester analogues (17.7 +/- 4.0 and 66.9 +/- 3.4% for 5b and 11a, respectively; 17.0 +/- 1.6 and 64.3 +/- 9.0% for 5c and 11b, respectively). The percent biliary excretion (15.8 +/- 4.4%) and plasma half-life in the rat (23.1 +/- 2.9 min) for 5a are consistent with the extended plasma half-life of the other phosphodiester derivatives. Taken together, the enhanced relaxivity and extended blood half-life of the phosphodiester derivatives support the concept of using endogenous albumin binding to achieve blood pool-like properties for small-molecule magnetic resonance imaging (MRI) contrast agents.
EPIX Medical, Inc., 71 Rogers Street, Cambridge, MA 02142-1118, USA. tmcmurry@epixmed.com
Thomas J
TJ
McMurry
David J
DJ
Parmelee
Hironao
H
Sajiki
Daniel M
DM
Scott
Hillori S
HS
Ouellet
Richard C
RC
Walovitch
Zoltán
Z
Tyeklár
Stéphane
S
Dumas
Paul
P
Bernard
Samuel
S
Nadler
Katarina
K
Midelfort
Matthew
M
Greenfield
Jeffrey
J
Troughton
Randall B
RB
Lauffer
D000818:Animals; D003287:Contrast Media / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D005682:Gadolinium; D019786:Gadolinium DTPA / Q000737:chemistry* / Q000493:pharmacokinetics*; D006207:Half-Life; D008279:Magnetic Resonance Imaging; D008297:Male; D009942:Organometallic Compounds / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D010755:Organophosphates / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D003287:Contrast Media; D009942:Organometallic Compounds; D010755:Organophosphates; D012709:Serum Albumin; D005682:Gadolinium; D019786:Gadolinium DTPA