| Coronary artery disease(CAD)is a leading cause of premature death and permanent disability.Myocardial perfusion imaging(MPI)with radiotracers is a non-invasive technique that shows the heart function(how well the heart muscle is pumping),and the areas of perfusion defects(the areas of heart muscle without enough blood flow).In order to accurately evaluate perfusion defects,the radiotracer must be taken up into myocardium in proportion to the regional blood flow.Therefore,an ideal perfusion radiotracer should have a high heart uptake with a stable myocardial retention,which linearly tracks the regional blood flow over a wide range flow rate(0—5 mL/min/g).99mTc-Teboroxime([99mTcCl(CDO)(CDOH)2B-Me]:CDOH2 = cyclohexanedione dioxime)has the highest first-pass extraction fraction among all 99mTc radiotarcers.However,its early clinical experiences with were disappointing because of its short myocardial retention.We have been interested in 99mTc(?)complexes[99mTcL(CDO)(CDOH)2B-R](L = Cl,F,N3 and SCN;R=alkyls or aryls)as radiotracers for heart imaging.We are particularly interested in these 99mTc(?)complexes because 99mTc-Teboroxime has very high first-pass extraction fraction,and shows the linear relationship between its heart uptake and regional blood flow rate up to 5 mL/min/g at 1-2 min after injection.In our present studies CDOH2-core can maintain the high initial heart uptake and different boronate caps are responsible for the heart uptake and myocardial retention time.As extended study,keeping the CDOH-core the new 99mTc(?)complexes[99mTcL(CDO)(CDOH)2B-R]with different coligands and boronate caps were explored,prepared in the kit formulations and evaluated as SPECT MPI.We are interested in three components with[99mTcL(CDO)(CDOH)2B-R](L=N3),[99mTcL(CDO)(CDOH)2B-R](L=Cl,R= formyl),and[99mTcL(CDO)(CDOH)2B-R](L=Cl,R= sulfonyl).1.[99mTcL(CDO)(CDOH)2B-R](L=N3)Novel 99mTc(?)-azide complexes[99mTc(N3)(CDO)(CDOH)2B-R](99mTc-ISboroxime-N3:R = IS;99mTc-MPboroxime-N3:R = MP;99mTc-PAboroxime-N3:R = PA;99mTc-PYboroxime-N3:R = PY;and 99mTc-Uboroxime-N3:R = 5U)were evaluated as heart imaging agents.Complexes[99mTc(N3)(CDO)(CDOH)2B-R](R = IS,MP,PA,PY and 5U)were prepared by ligand exchange between NaN3 and[99mTcCl(CDO)(CDOH)2B-R].Biodistribution and imaging studies were carried out in Sprague-Dawley rats.Image quantification was performed to compare their initial heart uptake and myocardial retention.99mTc-ISboroxime-N3,99mTc-PYboroxime-N3 and 99mTc-5Uboroxime-N3 were prepared with high RCP(93-98%)while the RCP of 99mTc-PAboroxime-N3 and 99mTc-MPboroxime-N3 was 80-85%.The myocardial retention curves of 99mTc-ISboroxime-N3,99mTc-PYboroxime-N3 and 99mTc-5Uboroxime-N3 were best fitted to the bi-exponential decay function.The half-time of the fast component was 1.6 ± 0.4 min for 99mTc-ISboroxime-N3,0,7± 0.1 min for 99mTc-PYboroxime-N3 and 0.9 ± 0.4 min for 99mTc-5Uboroxime-N3.The 2-min heart uptake from biodistribution studies followed the ranking order of 99mTc-ISboroxime-N3(3.60 ± 0.68%ID/g)>99mTc-PYboroxime-N3(2.35 ± 0.37%ID/g)?99mTc-5Uboroxime-N3(1.29 ± 0.06%ID/g).99mTc-ISboroxime-N3 had the highest 2-min heart uptake among 99mTc radiotracers revaluated in SD rats.High quality SPECT images were obtained with the right and left ventricular walls being clearly delineated.The best image acquisition window was 0-5 min for 99mTc-ISboroxime-N3.Both azide coligand and boronate caps had significant impact on the heart uptake and myocardial retention of complexes[99mTc(N3)(CDO)(CDOH)2B-R].2.[99mTcL(CDO)(CDOH)2B-R](L=Cl,R= formyls)we evaluated seven new 99mTc(?)complexes with formyl-containing boronate caps[99mTcCl(CDO)(CDOH)2B-R](99mTc-2Fboroxime:R-2-formylfuran-3-yl(2F);99mTc-3Fboroxime:R = furan-3-yl(3F);99mTc-5Fboroxime:R = 5-formyfuran-2-yl(5F);99mTc-HPboroxime:R = 6-hydroxylpyridin-2-yl(HP);99mTc-MPYboroxime:R = 5-methoxy-pyridin-3-yl;99mTc-PMboroxime:R = 1,5-pyrimidin-3-yl(PM),and 99mTc-4PYboroxime:R=pyridin-4-yl(4PY))for their potential as radiotracers for heart imaging.All new 99mTc(?)radiotracers except 99mTc-2Fboroxime were prepared with high radiochemical purity(RCP? 95%).The low RCP(?75%)for 99mTc-2Fboroxime is most likely caused by steric hindrance from the 3-formyl group.Biodistribution and imaging studies were carried out using SD rats.Planar image quantification was performed to compare their myocardial retention times.We found that the myocardial washout curves of new 99mTc(?)radiotracers were best fitted the "bi-exponential decay" function.The AUC values followed the general trend:99mTc-5Fboroxime(129 ± 6)>99mTc-3Fboroxime(114 ± 11)>99mTc-Teboroxime(104 ± 16)>99mTc-MPYboroxime(92 ± 18)>99mTc-4PYboroxime(77 ± 10)>99mTc-PMboroxime(68 ± 14)>99mTc-HPboroxime(62 ± 14).The 2-min heart uptake values from biodistribution studies follow the ranking order of 99mTc-5Fboroxime(3.75 ± 0.15%ID/g)?99mTc-MPYboroxime(3.73 ± 0.24%ID/g)>9mTc-PMboroxime(3.47 ± 0.15%ID/g)?99mTc-3Fboroxime?(3.25 ± 0.77%ID/g).The 5-min heart uptake of 99mTc-5Fboroxime(3.91 ± 0.09%ID/g)was almost identical to its 2-min heart uptake(3.75 ± 0.15%ID/g),and its 15-min heart uptake value(2.83 ± 0.08%ID/g)was well comparable to that of 99mTc-Teboroxime(3.00 ± 0.37%ID/g).It took about 5 min for 99mTc-5Fboroxime to approach the 1-min heart uptake value(3.5%ID/g)of 99mTc-Teboroxime,and-9.5 min to reach the 2-min heart uptake value(3.05%ID/g).The best image acquisition window is 0-5 min for 99mTc-5Fboroxime.However,high quality SPECT images were acquired in any of the 5-min window over the first 30 min after its administration.3.[99mTcL(CDO)XCDOH)2B-R](L = Cl,R = sulfonyls)In this study,sulfonyl-containing functional groups were used to optimize biodistribution properties of 99mTc(?)radiotracers[99mTcCl(CDO)(CDOH)2B-R](99mTc-3Sboroxime:R = 3S;99mTc-3SPboroxime:R = 3SP;99mTc-3MSboroxime:R = 3MS;99mmTc-3DMSboroxime:R = 3DMS;99mTc-3MSBboroxime:R = 3MSB;99mTc-3MMSboroxime;R=3MMS;99mTc-3MSAboroxime:R = 3MSA;99mmTc-3DMSAboroxime:R = 3DMSA;99mTc-4Sboroxime:R = 4S;99mTc-4MSboroxime:R = 4MS;99mTc-4MSBboroxime:R = 4MSB;and 99mTc-4PSboroxime:R = 4PS).All new 99mTc(?)radiotracers were prepared with high radiochemical purity(RCP>95%).Biodistribution and imaging studies were performed in Sprague-Dawley rats.Image quantification was used to compare their myocardial retention.We found that all new 99mTc(?)radiotracers had the initial heart uptake and myocardial retention times comparable to or better than those of 99mTc-Teboroxime.The 2-min heart values follow the general ranking order of 99mTc-3Sboroxime(5.38 ± 0.19%ID/g)>99mTc-3SPboroxime(3.66 ± 0.39%ID/g)?99mTc-4Sboroxime(3.31 ± 0.70%ID/g)?99mTc-3MSboroxime(3.26 ± 0.26%ID/g)>99mTc-4MSboroxime(2.16 ± 0.22%ID/g)?99mTc-4MSBboroxime(2.06 ± 0.16%ID/g)>99mTc-3MMSboroxime(1.81 ± 0.10%ID/g)>99mTc-3DMSboroxime(1.64 ± 0.07%ID/g)>9mTc-3DMSAboroxime(0.72 ± 0.03%ID/g).Among the new 99mTc(?)radiotracers evaluated in this study,the heart/liver ratios of 99mTc-3Sboroxime(H/L = 1.42 ± 0.07),99mTc-3SPboroxime(H/L = 1.24 ± 0.20)and 99mTc-4Sboroxime(H/L = 0.98 ± 0.29)were close to or better than that of 99mTc-Teboroxime(H/L=1.18 ± 0.21).The heart washout curves were best fitted with the bi-exponential equations.The calculated AUC(area under curve)values for 99mTc-3Sboroxime(AUC = 136),99mTc-3SPboroxime(AUC = 120)and 99mTc-4Sboroxime(AUC = 95)were much higher than those for 99mTc-Teboroxime(AUC = 71).It took-4 min for 99mTc-3SPboroxime and-8 min for 99mTc-3SBboroxime to approach the 2-min heart uptake value of 99mTc-Teboroxime(-3.0%ID/g).High quality SPECT images of rat hearts were acquired in any of the 5-min window over the first 30 min after injection of 99mTc-3Sboroxime and 99mTc-3SPboroxime,both of which have significant advantages over 99mTc-Teboroxime with respect to the initia heart uptake and myocardial retention times.The high heart uptake and long myocardial retention make it possible to use99mTc-3Sboroxime and 99mTc-3SPboroxie as radiotracers for SPECT MPI with standard and CZT-based ultrafast cardiac SPECT cameras.This statement was further supported by the result from SPECT/CT studies in pigs.As above,we found ligand-N3 and formyl or sulfonyl-containing boronate caps significantly impact on the heart uptake and retention time of the complexes[99mTcL(CDO)(CDOH)2B-R],the sulfonyl-containing boronate caps are the best effects.The combination of heart uptake and or long myocardial retention time makes it possible to use 99mTc-3Sboroxime and 99mTc-3SPboroxime as radiotracers for SPECT MPI with standard and CZT-based ultrafast cardiac SPECT cameras compared with 99mTc-ISboroxime-N3,99mTc-5Fboroxime and 99mTc-Teboroxime. |
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