Nucl. Med. Bioi. Vol. 18. No. 5, pp. 547-550, Inr. J. Radiat. A&. Instrum. Part B Printed in Great Britain. All rights reserved
1991 Copyright
0
0883-2897/91 53.00 + 0.00 1991 Pergamon Press plc
Lipophilic 99mTc-nitride Radiopharmaceuticals as Potential Myocardial Imaging Agents J. R. DILWORTH’, D. V. GRIFFITHS3,
C. M. ARCHER’*, 1. A. LATHAM’, J. D. KELLY’, D. C. YORK3, P, M. MAHONEY3 and B. HIGLEY’
‘Department of Chemistry and Biological Chemistry, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, ‘Amersham International plc, White Lion Road, Amersham, Bucks, HP7 9LL and ‘Department
of Chemistry, University of Keele, Keele, Staffs, ST5 5BG, England (Received 20 March 1990; in revised form 6 July 1990)
Monocationic %Tc-nitrido complexes of a variety of diphosphine ligands have been prepared and the in uino distribution of such cations has been examined in Sprague-Dawley rats. These complexes show initially high myocardial uptake with subsequent wash-out in this animal model. The lack of myocardial retention can be attributed to the facile in uiuo reduction of these cations.
Introduction Because of the superior nuclear properties of *Tc (y = 141 keV; l,12= 6.0 h) in comparison with 2a’TI (y = 68-82 keV, f,,2 = 73.1 h) the search for an effective 99”Tc-based myocardial imaging agent has received a good deal of attention recently (Deutsch et al., 1981; Piwnica-Worms et al., 1989; Thakur et al., 1984; Sarkar et al., 1989; Narra et al., 1988). Research efforts have centred on the investigation of the chemistry and biodistributions of lipophilic cations of technetium ever since the pioneering work on [Tc”’ L,Cl,]+ (L = diphosphine or diarsine ligand) complexes by Deutsch and co-workers (Deutsch et al., 1981). The work by Deutsch’s group highlighted the importance of the stability with respect to redox chemistry in determining the efficacy of 99mTccations as myocardial agents. In the [Tc”’ L2Clz]+ systems it was shown that in vivo reduction to the neutral species [Tc”L,Cl,]” led to rapid clearance of these agents from heart tissue (Vanderheyden et al., 1985). Nitride complexes of technetium are one class of compounds which might provide the basis for new heart radiopharmaceuticals (Baldas et al., 1986). Baldas and Bonnyman have presented a fair amount of information on the preparation of various neutral and anionic %“‘Tc based radiopharmaceuticals (Baldas et al., 1988). From previous work in our laboratories on the chemistry of the rhenium-nitride cations, [Re”N(L),Cl]+ (L = diphosphine or diarsine), we
were aware that the reduction of these cations occurs only at very negative potentials (E,!$ < - 1.0 V) (J. R. Dilworth, unpublished). Even given the expected decrease in reduction potential on going from complexes of the third-row transition metal rhenium to the second-row metal technetium of 200-300 mV (Hurst et al., 1981; Warren and Bennett, 1976), we expected that f&I” for cations of the general form, [Tc’N(L),Cl]+ (Fig. l), to be well outside the range accepted as being biologically accessible. We present here our studies, and the animal biodistributions, of some examples of this type of cation, the 99Tc chemistry of these systems is reported elsewhere (Archer, et al., 1989; Archer and Dilworth, in preparation).
Experimental Methods and materials
NH,*TcO, was obtained from Amertec IITM generators as saline solutions. The diphosphine ligands used were obtained commercially except for [MeOCH,P(Me)CH,], (P30) and (Me,PCH,),CHOMe (PL29) which were prepared according to the literature (Chiu et al., 1988).
*Author for correspondence.
Fig. 1. Structure of technetium-nitride 547
cations
548
J. R. DILWORTH et a/. Table L
1.Characterization of 199”TcN(L),X1+ comhxes
dmpe
dmpe
depe
dppe
PL29
P30
X MEKITLC % &
Cl
Br
Br
Cl
Cl
Cl
95 0.60
95 0.73
83 0.75
94 0.77
84 0.60
91 0.67
IrGL,I+ % &
3 0.00
5 0.06
16 0.09
-
16 0.00
4 0.00
Gelmooemenr +8.3
+8.3
(I)
Heat
(2)
NaN3, HCl
to
+4.8
0.00
+I.8
+3.4
dryness
CwmTc041-
C99mT~NC141-
L
\ C99mTcNCl (LIZ]+ Fig. 2
Complex synthesis
The precursor nitrido and the cationic complexes were prepared by the method of Baldas and Bonnyman (1985). Complex characterization
The purity of each preparation was monitored by a combination of TLC and gel electrophoresis. Results are summarized in Table 1. TLC
Thin-layer chromatography was performed using Whatman No. 1 paper and SO/SO(v/v) acetonitrile/ water to monitor the presence of reduced hydrolysed 99*Tc species. The species of interest and TcO; were monitored on Gelman ITLC-SG silica ITLC strips
(2 x 20 cm) using 2-butanone (MEK) and saline, respectively, as the mobile phase. Electrophoresis gels were prepared by heating 100mg of Agarose A (Pharmacia) in 10mL of 50 mM phosphate buffer (pH = 7.5) until the agarose dissolved. This solution was then poured onto a 5 x 20 cm glass plate to set. A hole was made in the gel for sample application and the plate developed using phosphate buffer as the electrolyte. Bromophthalein was used as an anionic marker. Gel movements are reported with respect to bromophthalein (gel movement for bromophthalein = - 10). Animal biodistributions
Six anaesthetized male Sprague-Dawley rats were given 0.1-0.2 mL (approx. 50 MBq) of solution by
Heart
PL29 =
1
Mei! P OMe Me, P >
P30 =
dmpe Cl
dmpeBr
PL29Cl
Time
depeBr
P3OCI
dppeC1
post-injection
Fig. 3. Rat biodistributions
for Tc-nitride
cations.
I
\
%Tc-nitrides
549
for myocardial imaging
i.v. (tail vein) injection. Half of the rats were sacrificed, dissected and the activity in the organs of interest counted after 2 and 60 min post-injection. The results are presented in Table 2.
Results and Discussion Synthesis of *Tc
complexes
The complex cations, [WmTcN(L)2Cl]‘, were prepared in a straightforward manner as depicted schematically in Fig. 2. The radiochemical purities (RPC) of the preparations as determined by TLC methods were routinely high (83-95%). The impurities commonly observed in these no-carrier-added preparations are believed to be the [Tc”‘Cl,(L),]+ species as shown by the comparison of chromatographic data with samples of authentic materials obtained by the literature methods (Neirinckx, 1983). Insignificant amounts of colloid (reduced hydrolysed technetium) and TcO; were observed in these preparations. Gel movements of these species confirmed that they were cationic. Biodistribution
data
The 2 and 60 min biodistribution data obtained for these complexes in Sprague-Dawley rats are given in Table 2. The high initial uptake by and subsequent low retention (Fig. 3) in the myocardial tissue parallels the behaviour of the known species [Tc”‘Cl,(L),]+ investigated by Gerson et al. (1983). This was very surprising in light of the expected stability with respect to reduction of the pcN(L),Cl]+ cations based upon comparisons made with the known rhenium congener, [ReN(dppe)zCl]+ (Johnson, 1973; Jabs and Herzog, 1972). Further investigations into the WTc chemistry of these cations has shown that the Tc-nitride phosphine complexes are indeed easily reduced (Archer and Dilworth, in preparation). Thus, the biodistribution data reflect the uptake of the initially injected cationic species which is reduced in uivo to a neutral Tc’” species [equation (l)] and then washed out of the myocardium. The in viva behaviour of the [TcN(P P)zCl]+ cations, therefore, parallels the behaviour observed for the [Tc”‘Cl,(P P)2]+ cations studied by the Deutsch group [99mT~VN(L)2Cl]+e-
p99W(L),C1]~.
(1)
References Archer C. M., Dilworth J. R., Kelly J. D. and McPartlin M. (1989) J. Chem. Sot. Chem. Commun. 375. Baldas J. and Bonnyman J. (1985) ht. J. Appl. Radiat. Isot. 36, 133. Baldas J. and Bonnyman J. (1988) Nucl. Med. Bio/. 15, 451 and refs therein. Baldas J., Bonnyman J. and Williams G. A. (1986) Inorg. Chem. 25, 150 and refs therein. Chiu K. W., Kelly J. D., Latham I. A., Griffiths D. V. and Edwards P. G. (1988) Euro Patent Appl. 0311 352 AI. Deutsch E., Glavan K. A., Sodd V. J., Nishiyama H., Ferguson D. L. and Lukes S. J. (1981) J. Nucl. Med. 22, 897.
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