J. Phys. Chem. 1995,99, 4900-4905
4900
Spin-Lattice Relaxation Enhancement of Water Protons by Manganese Porphyrins Complexed with Cyclodextrins? Sandip K. Sur and Robert G. Bryant" Chemistry Department, University of Virginia, McCormick Road, Charlottesville, Virginia 22901 Received: June 30, 1994; In Final Form: December 30, I994@
The addition of a-,p-, and y-cyclodextrins to tetrakis(4-su1fonatophenyl)porphine (TPPS4) and its manganese(11) and manganese(II1) complexes is characterized by optical and magnetic resonance spectroscopy. Microscopic binding constants for the formation of the cy~lodextrin-Mn*~'TPPS~ complexes are found to be 2.7, 94, and 41 M-' for the a-,p-, and y- complexes, respectively, assuming two identical binding sites that are noncompetitive. The formation of the cyclodextrin complex inhibits dimerization or polymerization of the porphyrins. The water proton nuclear magnetic spin-lattice relaxation rates are reported as a function of the magnetic field strength and the millimolar relaxivities for the cyclodextrin-Mn"'TPPS4 complexes are similar to those of the free Mn"'TPPS4 except at high magnetic fields where the rotational correlation times of the complex become important. However, the relaxivities for the cyclodextrin-Mn"TPPS4 complexes are quite high and not well described by the standard theories for paramagnetic relaxation. The shapes of the magnetic relaxation dispersion profiles are not Lorentzian and are more nearly approximated by the weaker magnetic field dependence of a translational diffusion model. However, such a model cannot simply account for the high relaxivities found.
Nuclear magnetic relaxation of water protons is central to control of image contrast and information content in magnetic resonance imaging.' Manganese-porphyrin complexes are effective nuclear spin relaxation agents2 and have received particular attention because they localize in tumors and facilitate sharp magnetic resonance image definition of the tumor b o u n d a r i e ~ . ~ -Tetrakis(4-sulfonatopheny1)porphine ~ (TPPS4) and several metal complexes are water soluble and well characterized. The aqueous chemistry is complicated by aggregation of both the free ligand and the metal complexes which may be driven by stacking interactions as well as axial ligand co~rdination.~-'~ The equilibria are pH and metal ion dependent and may also be altered by steric interactions imposed by substituents on the porphyrin. The manganese tetrakis(4-sulfonatopheny1)porphine complexes are water soluble and provide excellent models for understanding what controls relaxation efficiency in this class of complexes. The manganese(II1) complex is stable in air and is generally the oxidation state employed in relaxation agents However, the or contrast agent applications in vivo!-'6 manganese(I1) complex is more efficient because it has a longer electron relaxation time which limits efficiency for the manganese(II1) c o m p l e x e ~ .This ~ ~ ~ result is expected because the manganese(I1) complex has higher electronic symmetry." An interesting aspect of the manganese(I1) porphyrin complex relaxation efficiency is that it appears that outer-sphere relaxation contributions are larger than expected based on the usual models for rela~ation.~This observation raises the question of how to augment further possible effects of outer-sphere relaxation in addition to the usual approach of maximizing first coordination effects. The outer-sphere relaxation efficiency is determined by the translational diffusion coefficient of water in the vicinity of the metal complex and the distance of closest approach between the unpaired electron system and the relaxed proton
* To whom correspondence should be addressed. A preliminary report of this work was presented at the Experimental NMR Conference, April 10-16, 1994, Asilomar, CA. Abstract published in Advance ACS Abstracts, March 15, 1995. @
species.' *,I9 Control of local viscosity and macromolecular size may therefore affect both the translational or outer-sphere efficiency and the first coordination sphere efficiency. The cyclodextrins (CD), also called "Schardinger dextrins", are a class of cyclic oligosaccharides and contain six to eleven a-1,blinked D-glucose molecules. a-,,B-, and y-cyclodextrins are produced from enzymatic degradation of starch and correspond to cyclohexa-, cyclohepta-, and cyclooctaamylosewith a barrel structure, molecular weights of 972.9, 1135.0, and 1297.1 and intemal diameters of 4.5, 7.0, and 8.5 A, respectively. These 6-, 7-, and 8-membered species form stable hostguest clathrates with several compound^.^^-*^ which have drawn widespread attention in recent years because they serve to mimic biological systems and may be used to deliver d r u g ~ . ~ OA -~~ schematic representation of a cyclodextrin complex with a metalloporphyrin based on the crystal s t r u c t ~ r e s is ~ ~shown ~~' in Figure 1. The formation of such a complex should increase the rotational correlation time for the metal center and decrease the water translational diffusion coefficient, both of which should increase the relaxation efficiency of the compound. In this paper, we examine the association equilibria of the cyclodextrins with the TPPS4 and efficiency of manganese(I1) and manganese(III) TPPS4-cyclodextrin complexes in magnetically relaxing water protons. Experimental Section
The meso-tetrakis(4-sulfonatopheny1)porphine and its Mn(II1) complex, [Mn1I1TPPS4I3-,was purchased as sodium salt from Porphyrin Products, Inc. (Logan, UT). Na2S204 was obtained from Sigma Chemical Co. (St. Louis, MO), and the cyclodextrins were from Aldrich Chemical Co. Stock solutions were prepared in 50 mM HEPES buffer. [Mn"'TPPS4I3- was reduced with a 50-fold molar excess of dithionite over porphyrin under a nitrogen a t m ~ s p h e r e . ~Water ~ . ~ ~used in all experiments was routinely taken from a Bamsted Millipore Filtration System with both ionic and organic sections that used house deionized water as the feed. The pH was measured using an Orion Model 720A or a Coming Model 240 pH meter.
0022-365419512099-4900$09.00/0 0 1995 American Chemical Society
J. Phys. Chem., Vol. 99, No. 14, 1995 4901
Spin-Lattice Relaxation Enhancement of Water Protons
200
Figure 1. Molecular models of the [Mn"'TPPS4I4- and P-cyclodextrin structures showing their relative sizes for binding interactions. The structures were drawn using X-ray crystallographic parameters and coordinates for the [Mn1I1TPPS4I4-and P-cyclodextrin on a Silicon Graphics IRIS 4D35 computer using Insight I1 software from Biosym Technologies, San Diego, CA.
0.6
All electron paramagnetic resonance (EPR) measurements were carried out at ambient laboratory temperature using a Bruker ESP-300 spectrometer at X-band with 100 kHz magnetic field modulation with modulation amplitude of 5 G and microwave power level of 10 mW. DPPH was used to calibrate the magnetic field assuming a g factor of 2.0036. The nuclear magnetic relaxation rates were measured over a range of magnetic field strengths corresponding to proton Larmor frequencies between 0.01 and 30 MHz using a field-cycling spectrometer described e l s e ~ h e r e . ~The * ~ ~UV-visible ?~~ absorption spectra were obtained on a Hewlett-Packard Model 575 1 diode-array or a Varian Cary-4 spectrophotometer. The 'H and 13C NMR measurements were made either on a Varian Unity-Plus or a General Electric Omega spectrometer operating at a proton Larmor frequency of 500 or 400 MHz. The 2D-ROESY experiments were carried out at 499.88 MHz on the Varian Unity-Plus 500 spectrometer with a cw spin-lock field of 5.2 kHz and two 90°, pulses were applied before and after the mixing period of 200 ms to compensate for the undesirable effects that arises when the NMR peaks have different frequency offsets from the transmitter frequency.3432 scans were acquired for every tl value and 1024 x 5 12 data set was converted to 1024 x 1024 data set by zero-filling. The two-dimensional NOESY measurements were made at the same spectrometer frequency with a 100 ms mixing time.
0.2
Results and Discussion Complex Formation. All three cyclodextrins form hostguest complexes with the porphyrin, TPPS4, or its manganese derivatives as demonstrated by the observation of optical absorption spectra from the porphyrins shown in Figure 2a,b and the proton NMR spectra of the cyclodextrins shown in Figures 3 and 4. The UV-Visible Absorption Spectra. The UV-visible absorption spectra of the metal-free porphyrin ligand, TPPS4, have been measured in water as a function of concentration up to 1.1 x M. The monomeric porphyrin at low concentration is characterized by the Soret band at 414 nm and by Q-bands, especially at 5 18 and 636 nm. The formation of the
600
400
800
0.4
0.0 300
400
600
500
700
0.75 re.
-0.25 I 0.0 1.0 2.0 3.0 4.0
[Cyclodextrin], mM Figure 2. UV-visible absorption spectra from (a, top) 4.0 x M TPPS4 in the presence of 0, 1.0 and 5.0 x lov3M P-cyclodextrin and M Mn"'TPPS4 in the presence of 0, 5.4, 16.3, (b, middle) 7.0 x and 27.1 x M P-cyclodextrin in aqueous solution at ambient room temperature. The intensity of the 518 (i) and 645 (ii) nm bands from porphyrin TPPS4 with increasing concentration of P-cyclodextrin is shown in (c, bottom). (M) a; (0)P; (A)y.
dimer at high concentration of the porphyrin is accompanied by a red shift of the Soret band to 436 nm and by the appearance of a Q-band at 645 nm. These effects are consistent with the observations of Corsini and Herrmann. * From these results, we assign the Q-bands at 518 and 645 nm to the porphyrin monomer and dimer, respectively. The optical spectra demonstrate that TPPS4 in the millimolar concentration range primarily exists in equilibrium with the dimer or higher aggregates in aqueous solution below pH 7, a dimerization equilibrium constant of 15.4 x lo3 M-' has been reported.35 1935
4902 J. Phys. Chem., Vol. 99, No. 14, 1995
4.2
3.8
4.0
3.6
3.4 PPm
Figure 3. The 400 MHz proton NMR spectra of the 10 mM p-cyclodextrins in the presence of various amounts of TPPS4 at ambient room temperature; from top to bottom: 10.0, 5.0, 2.5, 1.0, 0.5, and 0 mM TPPSa.
5.2
4.6
4.0
3.4 ppm
Figure 4. Line-broadening in the 400 MHz proton NMR spectra of the 5 mM cyclodextrins in the presence of 1.25 mM paramagnetic Mn"'TPPS4 at ambient room temperature. The subscripts "free" and "bound" correspond to the absence and presence of Mn"'TPPS4.
The UV-visible absorption spectra of TPPS4 in the absence and in the presence of p-CD in aqueous solution are also consistent with the monomer-dimer equilibria as shown in Figure 2, a and c. As the concentration of p-CD increases, the 518 nm band increases and 645 nm band decreases in intensity with isosbestic points at approximately 318, 360, and 584 nm, and the Soret band undergoes blue shift implying monomer formation. Similar spectra were obtained from either a-CD or y-CD or from a mixture of CD's, although the spectral changes are smaller. Changes in the 5 18 and the 645 nm band are shown as a function of cyclodextrin concentration in Figure 2c. The increasing concentration of cyclodextrin destabilizes the dimer and promotes monomer formation, a hypothesis that will be supported below by additional NMR data. The absorption spectra of the paramagnetic complex, MnmTPPS4,in the absence and presence of P-CD are also shown in Figure 2b. These spectra are characterized by bands at 379 and 389 nm and a characteristic strong Soret band at 467 nm.36 The intensity of
Sur and Bryant these three bands from MnmTPPS4decrease almost linearly with increasing cyclodextrin concentration. There is, however, no observable shift in band positions or development of any new band with an increase in cyclodextrin concentration. This observation suggests that the Mn"'TPPS4 complex at neutral pH is primarily monomeric. This result is important in the context of the NMR relaxation experiments to follow because under the relatively high concentrationsused for the NMR work the Mnn1TPPS4complexes are essentially monomeric. Comparison of the concentration dependencies of the optical spectra (data not shown) demonstrates that the relative binding affinities of the cyclodextrins are in the same order for the Mn(II1) complex as for the metal-free TPPS4. The Stoichiometry of the Binding. The spectral evidence leaves no doubt that there is a binding interaction between the cyclodextrinsand the MnmTPPS4complex. Mosseri et al. have recently concluded that both Zn"TPPS4 and Fe"'TPPS4 form strong 1:4 complexes with P-CD in aqueous solution.37 Manka and Lawrence, on the other hand, have isolated a supramolecular complex in 85% yield with cyclodextrin and porphyrin, which is consistent with the 1:2 complex between cyclodextrin and porphyrin.38 Molecular modeling studies utilizing the X-ray crystallographic structures of cyclodextrin and porphyrin (see Figure 1) show that simultaneous binding of four cyclodextrin molecules to one porphyrin molecule is sterically unfavorable. The modeling studies suggest that the plane of the phenyl group is approximately perpendicular to the porphyrin plane as expected and that only two cyclodextrins bind simultaneously as concluded by Manka and Lawrence and shown in Figure 1. The data of Figure 2b were analyzed assuming independent and equivalent binding sites for two cyclodextrin molecules on the porphyrin. Assuming that not more than two cyclodextrins may bind to the porphyrin simultaneously and that these sites are identical, the microscopic binding constants for each binding to Mn"ITPPS4 are 2.7, 94, and 41 M-' for a-,/3-, and y-cyclodextrin, respectively. Therefore, in a solution of MnII'TPPS4 containing 10 mM P-cyclodextrin, each porphyrin has on average at least one cyclodextrin bound. Similar experiments with the metal-free porphyrin yield a microscopic binding constant of 440 M-I for the P-cyclodextrin. NMR Spectroscopy. The proton NMR spectrum of a 2.5 mM solution of TPPS4 in D2O at ambient temperature consists of two doublets ( 3 J = ~ 8.24 ~ Hz) from the ortho (6,8.47 ppm) and meta (6, 8.87 ppm) phenyl protons and one singlet (6,9.08 ppm) from all four P-pyrrole protons. These resonances shift downfield with the addition of cyclodextrins which may be explained by a shift to monomer from associated species. Figure 3 shows the proton NMR spectra of the cyclodextrins between 3.5 and 4.5 ppm as the concentration of porphyrin is increased. Although all resonances are affected, the H-3 and H-5 protons are strongly shifted and broadened by binding to the porphyrin. The Mn"'TPPS4 is paramagnetic and cyclodextrin binding results in broadening and larger shifts of the proton NMR lines of the cyclodextrin resonances as shown in Figure 4. The effects are most pronounced for the P-cyclodextrin which is consistent with the relative order of the binding constants. The cyclodextrin resonances in the I3C NMR spectrum of the TPPS4-P-cyclodextrin complex are shown in Figure 5. The assignment of the protonated carbon resonances were made by selective low power proton decoupling and are consistent with earlier reports on other porphyrin^^^,^^ and c y c l ~ d e x t r i n s . ~ ' ~ ~ ~ When the concentration of the cyclodextrin is low, the carbon resonance of all the porphyrin resonances broaden which is consistent with exchange of the cyclodextrin among porphyrin phenyl positions in a time short compared with approximately
Spin-Lattice Relaxation Enhancement of Water Protons
110
100
90
J. Phys. Chem., Vol. 99, No. 14, 1995 4903
80
60 PPm
70
Figure 5. The 125.7 MHz I3C NMR spectra of 2.5 mM /3-cyclodextrin in the absence of (a) and presence of (b) 2.5 mM TPPS4 at ambient room temperature.
33 ms.21933The I3C resonances of 2.5 mM TPPS4 in the presence of 2.5 mM /?-cyclodextrinappear at 146.3 (a-carbon), 145.7, 142.5, 139.9 (ortho, 2 J =~ 162 ~ Hz), 131.3 @-pyrrole *JCH= 180 Hz), 126.6 (meta, *JCH= 166 Hz), and 123.3 (meso) ppm. In the cyclodextrin-free solution, the a-carbon peak appears at 146.2 ppm. As shown in Figure 5a, the carbon resonances of the free /3-cyclodextrin appear at 102.97 (C-1), 82.25 (C-4), 74.19 (C3), 73.19 (C-5), 72.92 (C-2), and 61.40 (C-6) ppm. The corresponding peaks of the free a-cyclodextrin are at 102.53, 82.35, 74.44, 73.15, 72.83, and 61.57 ppm. When equimolar TPPS4 is present in the solution (see Figure 5b), the 13Cpeaks shift to 103.15 (C-1, *JCH = 169 Hz), 82.42 (C-4, 2 J =~ 145 ~ Hz), 74.51 (C-3, *JCH= 148 Hz), 72.99 (C-5 and C-2, *JCH = 147 Hz), and 61.36 (C-6, 2 J ~ = H 145 Hz) ppm. The prominent feature of the binding is about 0.32 ppm deshielding of the C-3 and 0.21 ppm shielding of C-5 resonances so that the peaks from C-5 and C-2 overlap at 72.99 ppm. Addition of excess TPPS4 did not appreciably shift the carbon resonances of the cyclodextrins. Intermolecular binding interactions are directly demonstrated by observation of intermolecular nuclear Overhauser effects between the binding partners. No nOe cross peaks were observed in the 2D-NOESY spectrum of a 2 mM solutian of TPPS4 in the presence of 8 mM /?-cyclodextrin. The cyclodextrin, the porphyrin, and the complex are of intermediate size so that at 500 MHz the reorientation time is nearly the reciprocal of the Larmor frequency where NOESY cross peaks are near zero amplitude. However, rotating frame nOe spectra of the same solution yielded a cross peak between the H-5 proton of the cyclodextrin and the ortho-protons of the phenyl rings on the porphyrins, which is consistent with the binding model of Figure 1. Electron Spin Resonance. Both manganese complexes are high spin. The Mn(1II) complex with S = 2 has very short electron relaxation time and is consequently EPR silent even at 77 K. The Mn(II) complex with S = 2.5, on the other hand, has longer electron relaxation time consistent with the observa-
VI
k
I
I
,1.o
I
I
I
I
2.0
I
3.0
H-
1
I
4.0
J 5.0 kG I
Figure 6. X-band electron paramagnetic resonance spectra of (a) [Mnt1TPPS4I4-and (b) [Mn"TPPS4l3- at 77 K. The peaks marked with an asterisk at g 2 are from an impurity in the cavity.
-
tion of their epr spectra of axial symmetry at 77 K as shown in Figure 6 measured without any added cyclodextrin. The spectra with added a-, /3-, and y-cyclodextrins are essentially similar to that without added cyclodextrin and to other manganeseporphyrin systems. All spectra have two signals at gi = 5.9 and gll = 2.0 with well resolved hyperfine splittings from the manganese nucleus (I = 512). The zero-field parameters D and E define axial and rhombic distortions and their ratio EID in these Mn(I1) porphyrins is small and is 10.01.43,44In the g 6 region, there are seven hyperfine lines and the value of D is approximately 0.5 cm-' and the hyperfine coupling constants are A1 = 78.6 G and All = 117.5 G. The consequence of this spectrum is that the zero field splitting provides essentially a powder pattern for the EPR in the solutions studied because the rotational motion of the metal center is not rapid compared with the breadth of the EPR spectrum. Thus, the slow motion models for the spin-lattice relaxation induced in
-
4904 J. Phys. Chem., Vol. 99, No. 14, 1995
-5in r
E
2o
15
Sur and Bryant
L 4 I ow
I
L
I
.-s .-> X 4-
([I -
?it
0
c
2 a
O I
0.01
LL I
I
0.1 0
1.00
- 0
1
10.00
100.00
0.01
Proton Larmor Frequency, MHz Figure 7. Water proton spin-lattice relaxation rate of [Mn"'TPPS4I3in the presence of 10-fold molar excess of cyclodextrins at pH 7 plotted against the magnetic field strength expressed as the proton Larmor frequency at 298 K: (0)no added cyclodextrin, (A) a-cyclodextrin, (0) P-cyclodextrin, (0)y-cyclodextrin.
the water protons are more appropriate than the more standard Solomon, Bloembergen, Morgan e q ~ a t i o n s . ~ ~ - ~ ' Magnetic Relaxation Dispersion. The water proton relaxivities for aqueous solutions of Mn"'TPPS4 complexes are shown in Figure 7 as a function of magnetic field strength plotted as the proton Larmor frequency for different cyclodextrins present at the level of 10 mh4. At low magnetic field strengths there is little difference in the water proton relaxation rates which is consistent with earlier work and characteristic of the situation where the electron spin relaxation rate controls the modulation of the electron-nuclear coupling. It is interesting to note in this regard that the different cyclodextrins make very little difference in the zero field electron spin relaxation rate, which indicates that intermolecular mechanisms or bulk reorientation rates do not affect the electron relaxation rate for this complex very much. Further, since all the cyclodextrins have essentially the same rate at low field strengths, the phenyl ring participation in whatever the intramolecular processes are that drive electrons spin relaxation is not important. The differences in the relaxation rates observed at higher magnetic field strengths are consistent with the changes in the rotational correlation times associated with the binding of the cyclodextrins. In this case the ,8-cyclodextrin is the most efficient relaxation agent at 20 MHz which is consistent with this complex having the longest rotational correlation time. Independent measurements of this parameter for the zinc complex employing carbon NMR relaxation place the rotational correlation time for the cyclodextrin-free solutions at 275 ps. The relaxation profiles change dramatically when the Mn111TPPS4is reduced to the manganese(I1)compound as shown in Figure 8. Cyclodextrin binding increases the relaxivities in each case as shown in Figure 9; however, the y-cyclodextrin is the most efficient, which is not in the order of the binding constants. The largest complex should be the y-cyclodextrin, which is consistent with this complex having the highest rate; however, this order is different from that found in Figure 7. An additional possible contribution to the relaxation efficiency of the cyclodextrin complexes may be made by water that is transiently associated with the lumen of the cyclodextrin in the cyclodextrin-porphyrin complexes; however, we have no direct evaluation of this possibility. The low-field relaxivities imply that the relaxation efficiency of these complexes is not apparently severely limited by the electron relaxation rate as it is in the manganese(II1) case. Were the correlation time simply the
0.10
1.00
100.00
10.00
Proton Larmor Frequency, MHz Figure 8. Water proton spin-lattice relaxation rate of [Mn"TPPS4I4in the presence of 10-fold molar excess of cyclodextrins at pH 7 plotted against the magnetic field strength expressed as the proton Larmor frequency at 298 K: (0)no added cyclodextrin, (A) a-cyclodextrin, (0) P-cyclodextrin, (0)y-cyclodextrin. h
16
12 8
4 1 0
1
I
1
2
4
6
I
8
10
12
[p-CD] / [Mn(ll)TPPSJ Figure 9. Spin-lattice relaxation enhancement of water protons from [Mn1TF'PS4]4- in the presence of various molar excess of P-cyclodextrin at pH 7 measured at (0) 0.01, (0) 0.1, (0) 10, and (A) 30 MHz frequency at 298 K.
rotational correlation time for these complexes, the inflection point for the dispersion curves would be in the range of 0.8 MHz or lower, which is clearly not the case for the data of Figure 8. An important feature of all the data in Figure 8 is that the shapes of the relaxation dispersion plots are not predicted by any of the first coordination sphere models reported including the more complete models. Even though the EPR spectrum demonstrates that there is a significant spread of electron Larmor frequencies, the effect on the breadth of the inflection region of the relaxation dispersion profile is minor compared with the relatively weak dependence demonstrated in Figure. 8. If we consider the low-field limiting rates only, it is possible to select water proton-Mn(I1) distances that do not violate the crystal structure which with an appropriate choice of electron relaxation rate and water proton exchange rate yield rates equivalent to those found in Figure 8. However, the important difficulty of the relaxation dispersion shape remains. In a previous report on the cyclodextrin-free solutions, this situation was discussed in terms of increased contributions from outer-sphere effects and the possible failure of the point dipole approximation, Le., the possible importance of electron delocalization into the porphyrin ring.48 Were this the case, one would expect that the addition of the cyclodextrins to the complex would not only
J. Phys. Chem., Vol. 99, No. 14, 1995 4905
Spin-Lattice Relaxation Enhancement of Water Protons slow the rotational motion of the complex and possibly contribute to the first coordination sphere relaxivity, but the sugar residues may also interact with the water by hydrogen bonding more efficiently and slow its translational diffusion in the vicinity of the metal center. Based on results of earlier studies of outer sphere contributions to the water proton relaxation,2 a change in the water diffusion coefficient in the vicinity of the metal center by a factor of 10 would approximately account for the magnitude of the relaxation rates; however, we have no direct evidence that this change occurs. Thus, the higher efficiency of the cyclodextrin complexes is consistent with an increase in the translational contribution to the relaxivity and the general shape of the relaxation dispersion plots; however, the inflection region of the dispersion plots in Figure 8 is at rather high magnetic field strengths for the magnitude of the change in the water diffusion coefficient required if the standard outer-sphere model is used, which suggests participation of the electron relaxation time in the effective correlation time for the electron-nuclear coupling. Nevertheless, the relaxation rates for these solutions are high and additional interactions besides those normally considered may be important. At present we have no quantitative way to assess how this model may change if the electron is significantly delocalized in the porphyrin ring or if additional water molecules are transiently bound in association with the porphyrincoordinated cyclodextrins. Clearly, the latter may increase relaxation efficiency. In summary, the addition of cyclodextrins to aqueous solutions of MnIITPPS4 yields macromolecular complexes that enhance the water proton spin-lattice relaxation rates by nearly a factor of 2 over the cyclodextrin-free solutions. The magnetic field dependence of the proton relaxation rate is not well described by the usual first coordination sphere theories. The shape of the relaxation dispersion profile suggests that translational contributions to the electron-nuclear coupling are significant possibly because the carbohydrate in the metal center environment slows the relative translational motions.
Acknowledgment. We gratefully acknowledge Professor W. Robert Scheidt, Chemistry Department, University of Notre Dame, for helpful discussions and for providing X-ray data on the manganese(II) porphyrin. References and Notes (1) Mansfield, P.; Morris, P. G. NMR Imaging in Biomedicine; Academic Press: New York, 1982. (2) Hemlndez, G.: Bryant, R. G. Bioconjugate Chem. 1991, 2, 394 and references cited therein. (3) Chen, C.-W.; Cohen, J. S.; Meyers, C. E.; Sohn, M. FEBS Lett. 1984, 168, 70. (4) Lyon, R. C.; Faustino, P. J.; Cohen, J. S.; Katz, A.; Momex, F.; Colcher, D.; Baglin, C.; Koenig, S. H. Magn. Reson. Med. 1984, 4 , 24. (5) Fiel, R. J.; Musser, D. A.; Mark, E. H.; Mazurchuk, R.; Alletto, J. J. Magn. Reson. Imaging 1990, 8, 255. (6) Fiel, R. J.; Button, T. M.; Gilani, S.; Mark, E. H.; Musser, D. A,; Henkelman, R. M.; Bronskill, M. J.; van Heteren, J. G. Magn. Reson. Imaging 1987, 5, 199.
(7) Ogan, M. D.; Revel, D.; Brasch, R. C. Invest. Radiol. 1987, 22, 822. (8) Furmanski, P.; Longley, C. Cancer Res. 1988, 48, 4604. (9) White, W. I. In The Porphyrins; Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. 5, Chapter 7. (IO) Kadish, K. M.; Maiya, G. B.; Araullo, C.; Guilard, R. Inorg. Chem. 1989, 28, 2725. (11) Willigen, H.; Chandrasekhar, T. K.; Das, U.; Ebersole, M. H. In Porphyrins, Excited Stares and Dynamics: Gouterman, M., Rentzepis, P. T., Straub, K. D., Eds.; American Chemical Society: Washington, DC, 1986; pp 140-153. (12) Chandrasekhar, T. K.; Willigen, H.; Ebersole, M. H. J. Phys. Chem. 1984, 88, 4326-4332. (13) Pastemack, R. F.; Huber, P. R.: Boyd, P.: Engasser, G.; Francesconi, L.; Gibbs, E.; Fasella, P.; Venturo, G. 6.;Hinds,L. J. Am. Chem. SOC. 1972, 94, 951 1. (14) Fleischer, E. B.; Palmer, J. M.; Srivastava, T. S.; Chatterjee, A. J. Am. Chem. SOC. 1971, 93, 3162. (15) Krishnamurthy, M.; Sutter, J. R.; Hambright, P. J. Chem. Soc., Chem. Commun. 1975, 13. (16) Furmanski, P.: Longley, C. Cancer Res. 1988, 48, 4604. (17) Bertini, I.; Luchinat, C. NMR of Paramagnetic Molecules in Biological Systems; Benjamin Cummings: Menlo Park, CA, 1986. (18) Hwang, L.; Freed, J. H. J. Chem. Phys. 1975, 63, 4017. (19) Freed, J. H. J. Chem. Phys. 1978, 68, 4034. (20) Szejtli, J. Cyclodextrins and their Inclusion Complexes; Akademiiai Kiado: Budapest, 1982. (21) Saenger, W. Angew. Chem., Int. Ed. Engl. 1980, 19, 344. (22) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry; SpringerVerlag: Berlin, 1978. (23) Tabushi, I. In Inclusion Compounds; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Eds.; Academic Press: London, 1984; Vol. 3, p 445. (24) James, W. J.; French, D.; Fundle, R. E. Acta Crystallogr. 1959, 12, 385. (25) Flohr, K.: Paton, R. M.; Kaiser, E. T. J. Am. Chem. Sac. 1975, 97, 1209-1217. (26) Formoso, C. Biopolymers 1974, 13, 909-917. (27) Tabushi, I.; Kuroda, Y.; Mizutani T. Tetrahedron 1984, 40, 545552. (28) Breslow, R.; Greenspoon, N.; Guo, T.; Zarzycki, R. J. Am. Chem. SOC.1989, 111, 8296. (29) Rademacher, J. T.; Czamik, A. W. J. Am. Chem. SOC.1993, 115, 3018. (30) Williamson, M. M.; Hill, C. L. Inorg. Chem. 1987, 26, 4155. (31) Lindner K.; Saenger, W. Carbohydrate Res. 1982, 99, 103-115. (32) Hambright, P.; Chock, P. B. Inorg. Chem. 1974, 13, 3029. (33) Hemandez. G. H.: Brittain. H. G.: Tweedle. M. F.: Brvant. R. G. Ino;g.’Chem. 1990, 29, 985. (34) Griesinger C.: Emst, R. R. J. Mag. Reson. 1987. 75, 261-271. (35) Corsini:A.; Henmann, 0. TalanG 1986, 33, 335-339. (36) Harriman, A,; Porter, G. J. J. Chem. Soc., Faraday Trans. 1979, 275, 1532 and 1543. (37) Mosseri, S.; Mialocq, J. C.; Perly, B.; Hambright, P. J. Phys. Chem. 1991, 95, 2196 and 4659. (38) Manka, J. S.; Lawrence, D. S. J. Am. Chem. SOC.1990,112,24402442. (39) Abraham, R. J.; Hawkes, G. E.: Hudson, M. F.; Smith, K. M. J. Chem. Soc., Perkin Trans. 2 1975, 204. (40) Milgrom, L. R. J. Chem. SOC.,Perkin Trans. 1 1984, 1483. (41) Colson, P.; Jennmings, H. J.; Smith, I. C. P. J. Am. Chem. SOC. 1974, 96, 8081. (42) Behr, J. P.; Lehn, J. M. J. Am. Chem. SOC. 1976, 98, 1743. (43) Dowsing, R. D.; Gibson, J. F. J. Chem. Phys. 1969, 50, 294. (44) Yonetani, T.; Drott, H. R.; Leigh, J. S., Jr.; Reed, G. H.; Waterman, M. R.; Asakura, T. J. Biol. Chem. 1970, 245, 2998-3003. (45) Solomon, I. Phys. Rev. 1955, 99, 559. (46) Bloembergen, N. J. Chem. Phys. 1957, 27, 572. (47) Bloembergen, N.; Morgan, L. 0. J. Chem. Phys. 1961, 34, 842. (48) Unger, S. W.; Jui, T.; La Mar, G. N. J. Mag. Reson. 1985, 61, 448. JP941661J
