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Sulfonyl-Containing Boronate Caps for Optimization of Biological Properties of 99mTc(III) Radiotracers [99mTcCl(CDO) (CDOH)2B-R] (CDOH2 = Cyclohexanedione Dioxime) Zuoquan Zhao, Min Liu, Wei Fang, and Shuang Liu J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.7b01412 • Publication Date (Web): 29 Nov 2017 Downloaded from http://pubs.acs.org on November 29, 2017

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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Journal of Medicinal Chemistry

Sulfonyl-Containing Boronate Caps for Optimization of Biological Properties of 99mTc(III) Radiotracers [99mTcCl(CDO)(CDOH)2B-R] (CDOH2 = Cyclohexanedione Dioxime)

Zuo-Quan Zhao,1 Min Liu,2 Wei Fang,1 and Shuang Liu2*

1

Department of Nuclear Medicine, Fuwai Hospital, the National Center for Cardiovascular

Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, China, 100037 2

School of Health Sciences, Purdue University, IN 47907, USA

RUNNING TITLE: Novel 99mTc(III) Complexes as Heart Imaging Agents

# These authors contributed equally to this work. *Correspondence should be addressed to: Dr. Shuang Liu, School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, Phone: 765-494-0236, Fax 765-496-1377, Email: [email protected]; or Dr. Wei Fang, Department of Nuclear Medicine, Fuwai Hospital, the National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167 North Lishi Road, Xicheng District, Beijing, China, 100037. Email: [email protected].

1

ACS Paragon Plus Environment

Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ABSTRACT: In this study, different boronate caps were used to optimize biodistribution properties of radiotracers [99mTcCl(CDO)(CDOH)2B-R] (1: R = 3S; 2: R = 3SP; 3: R = 3MS; 4: R = 3DMS; 5: R = 3MSB; 6: R = 3MMS; 7: R = 3MSA; 8: R = 3DMSA; 9: R = 4S; 10: R = 4MS; and 11: R = 4MSB). Among the eleven new

99m

Tc radiotracers, 2 shows the most promising

characteristics of an optimal heart imaging agent. Its initial heart uptake is close to that of 99mTcTeboroxime, but its heart retention time is significantly longer. Its heart/liver, heart/lung and heart/muscle ratios are also better than those of with 2 in SD rats is better than that with

99m

Tc-Teboroxime. The SPECT image quality

99m

Tc-Teboroxime. The high initial heart uptake, long

heart retention and high heart/background ratios make 2 an excellent SPECT radiotracer for MPI.

KEY WORDS:

99m

Tc(III) complexes,

99m

Tc-Teboroxime derivatives, and myocardial perfusion

imaging

2


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INTRODUCTION Coronary artery disease (CAD) arises from the gradual narrowing of coronary arteries and the decrease of blood flow due to build-up of cholesterol-containing deposits (plaque). Complete blockage of coronary arteries may cause myocardial infarction (commonly known as heart attack). Myocardial perfusion imaging (MPI) with radiotracers is a noninvasive technique to show the heart function (how well the heart muscle is pumping), and areas of perfusion defects (the areas of heart muscle without enough blood flow).1-6 In order to evaluate perfusion defects with accuracy, the radiotracer heart uptake must be proportion to regional blood flow.3-10 Precise measurement of the blood flow is of great clinical importance in identifying CAD, defining severity of disease, assessing myocardial viability, establishing the need for surgical intervention, and monitoring treatment efficacy. An ideal perfusion radiotracer should have the biodistribution properties controlled by blood flow, rather than receptor binding or metabolism. It should also have a high initial heart uptake, a stable myocardial retention and the capability to track regional blood flow at 0 – 5 mL/min/g in a linear fashion. Stable myocardial retention is important to maintain this linear relationship. Rapid decrease of heart uptake often reduces the myocardial extraction and leads to the loss of linear relationship between radiotracer heart uptake and myocardial blood flow rate.7,10 We have been interested in

99m

Tc(III) complexes [99mTcL(CDO)(CDOH)2B-R] (CDOH2 =

cyclohexanedione dioxime; L = Cl, F, N3 and SCN; R = alkyls or aryls) as heart imaging agents,11-14 because [99mTcCl(CDO)(CDOH)2B-CH3] (99mTc-Teboroxime) has high first-pass extraction fraction,15-19 and shows a linear relationship between its heart uptake and myocardial blood flow at 1 – 2 min postinjection (p.i.).20 Boronate caps are shown to have significant impact on biological properties of

99m

Tc(III) radiotracers [99mTcCl(CDO)(CDOH)2B-R].12,14 Among the 3



radiotracers

evaluated

([99mTcCl(CDO)(CDOH)2B-PA]: ([99mTcCl(CDO)(CDOH)2B-5F]:

in

our PA

5F

=

studies,11-14

previous

=

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1H-pyrazol-3-yl)

2-formylfuran-5-yl)

99m

Tc-PAboroxime

99m

and

show

Tc-5Fboroxime

the

most

favorable

biodistribution properties for heart imaging.12,14 However, they both have relatively high liver uptake.12,14 Therefore, there is a continuing need to minimize the liver uptake and maximize heart/liver ratios while maintaining the high heart uptake.

Figure 1. Structures of complexes [99mTcCl(CDO)(CDOH)2B-R] (1: R = 3S; 2: R = 3SP; 3: R = 3MS; 4: R = 3DMS; 5: R = 3MSB; 6: R = 3MMS; 7: R = 3MSA; 8: R = 3DMSA; 9: R = 4S; 10: R = 4MS; and 11: R = 4MSB) under evaluation for their potential as radiotracers for heart imaging. As a continuation of our previous studies,11-14 we now present evaluation of novel

99m

Tc(III)

complexes [99mTcCl(CDO)(CDOH)2B-R] (Figure 1: 1: R = 3S; 2: R = 3SP; 3: R = 3MS; 4: R = 3DMS; 5: R = 3MSB; 6: R = 3MMS; 7: R = 3MSA; 8: R = 3DMSA; 9: R = 4S; 10: R = 4MS; and 11: R = 4MSB) as new radiotracers for heart imaging. Various sulfonyl-containing boronate caps are utilized to modify the biological properties of their corresponding

99m

Tc(III)

radiotracers because of their structural diversity. The ultimate goal is to discover and develop an optimal

99m

Tc radiotracer with a high initial heart uptake, good heart/liver ratios, and the

myocardial retention time substantially longer than that of

99m

Tc-Terboroxime. The high initial

heart uptake and long myocardial retention will help maintain the linear relationship between the radiotracer heart uptake and myocardial blood flow rate.20 4


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RESULTS Radiochemistry. All new radiotracers 1 – 11 are prepared according to Chart I. Heating at 100 oC is required in order to complete radiosynthesis. Table 1 summarizes their radiochemical purity (RCP) data and HPLC retention times. Their RCP is 95 – 98% without post-labeling chromatographic purification. They are all stable in solution for > 6 h (Figure SI). The HPLC retention times follow the general ranking order of 11 (15.5 min) > 5 (15.3 min) > 8 (13.3 min) > 7 (13.0 min) > 6 (12.8 min) > 1 (12.4 min) ~ 9 (12.5 min) > 3 (11.5 min) ~ 7 (11.5 min) ~ 10 (11.5 min) > 2 (8.5 min). Longer HPLC retention time (Table 1) indicates that the radiotracer is more lipophilic under the conditions used in this study. Chart I. Radiosynthesis of New 99mTc(III) Radiotracers 1 – 11.

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Table 1. HPLC retention times and RCP data for 1 – 11. 99m

HPLC Retention Time (min)

RCP (%)

[99mTcCl(CDO)(CDOH)B-3S] (1)

12.4

>95%

[99mTcCl(CDO)(CDOH)B-3SP] (2)

8.5

>95%

[99mTcCl(CDO)(CDOH)B-3MS] (3)

11.5

>95%

[99mTcCl(CDO)(CDOH)B-3DMS] (4)

13.0

>95%

[99mTcCl(CDO)(CDOH)B-3MSB] (5)

15.3

>95%

[99mTcCl(CDO)(CDOH)B-3MMS] (6)

12.8

>95%

[99mTcCl(CDO)(CDOH)B-3MSA] (7)

11.5

>95%

[99mTcCl(CDO)(CDOH)B-3DMSA] (8)

13.2

>95%

[99mTcCl(CDO)(CDOH)B-4S] (9)

12.5

>95%

[99mTcCl(CDO)(CDOH)B-4MS] (10)

11.5

>95%

[99mTcCl(CDO)(CDOH)B-4MSB] (11)

15.5

>95%

Tc(III) Complex (Code Number)

Dynamic Planar Imaging. Dynamic planar imaging was performed in SD rats for 1 – 11. Their initial heart uptake and washout kinetics are most important parameters in evaluation of new

99m

Tc radiotracers. Table 2 lists image quantification data and the area under curve (AUC)

values. Their myocardial washout curves are best fitted the biexponential function, from which their 1-min heart uptake and AUC values are calculated. Among the 99mTc radiotracers evaluated in this study, 4 and 8 have the highest AUC values. Radiotracers 1, 2 and 9 show the 1-min heart uptake and AUC values that are higher than those of

99m

Tc-Teboroxime. It is worth noting that

the heart radioactivity obtained from planar image quantification include the radioactivity in both blood pool and myocardium. Thus, biodistribution studies were performed to compare their in vivo distribution properties at 2-min p.i. in SD rats (200 – 225 g). 6


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Table 2. Image quantification data for 1 – 11 to compare their heart uptake and washout kinetics. Their initial heart uptake is defined as the %ID heart uptake at 1 min p.i. Experimental data were obtained from 4 – 5 animals for each radiotracer. AUC values are calculated as according to their respective bi-exponential equations. Initial Heart Uptake (%ID)

AUC Value

R2 Value

6.0±0.3

135±11

0.9920

1

4.7±0.7

141±10

0.9685

2

4.9±1.0

134±29

0.9609

3

4.3±0.7

104±8

0.9609

4

4.9±0.7

141±10

0.9685

5

4.9±0.6

114±12

0.9810

6

5.1±0.7

110±12

0.9601

7

5.4±0.8

143±17

0.9159

8

6.0±0.6

102±7

0.9733

9

4.5±0.7

101±6

0.9571

10

5.4±0.8

123±7

0.9355

11

6.0±0.3

135±11

0.9920

Radiotracer 99m

Tc-Teboroxime

Comparison of Biodistribution Data. Table SI1 lists the selected 2-min biodistribution data for 1 – 4, 6 and 8 – 11. Figure 2 compares their 2-min uptake in the heart and liver. The 2-min heart values follow the general ranking order of 1 > 2 ~ 3 ~ 9 > 10 ~ 11 > 6 > 7 > 8. The liver uptake follows the order of 8 ~ 2 < 9 ~ 1 < 10 ~ 3 ~ 6 ~ 10 < 4. All new 99mTc radiotracers have low lung uptake. There is no clear relationship between the lipophilicity (Table 1) and heart uptake (Table SI1) of a specific radiotracer. However, more lipophilic radiotracers tend to have higher liver uptake values. Since 1, 2 and 9 have the heart/liver ratios close to or better than that of 99mTc-Teboroxime,11 they were selected for full-scale biodistribution studies to compare their heart retention times and pharmacokinetics from the blood and normal organs.

7



Figure 2. Comparison of uptake values of 1 – 4, 6, and 8 – 11 in the heart (A) and liver (B) at 2 min p.i. in SD rats (n = 3 – 4). Higher heart uptake suggests a better radiotracer. Lower liver uptake indicates less background radioactivity.

8


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Figure 3. A: Linear relationship between 2-min heart uptake and blood radioactivity for 1 – 4, 6 and 8 – 11. The 2-min heart uptake and blood radioactivity values were reported as an average from biodistribution studies. Standard error bars were not shown for its clarity. B: Direct comparison of the % of 1 – 3 and 8 - 11 binding to RBCs and plasma proteins. All experimental data were obtained from the blood samples used in biodistribution studies in SD rats (n = 3 – 4). C: Linear relationship between 2-min heart uptake and % albumin binding for 1 – 3 and 8 - 11.

9



Page 10 of 36

Impact of Blood Radioactivity. Inspection of biodistribution data for new 99mTc radiotracers evaluated in SD rats (Table SI1) showed that radiotracers 1, 2 and 9 all have low radioactivity in the blood and their 2-min heart uptake is higher than that of

99m

Tc-Teboroxime. There is an

inverse linear relationship between the 2-min heart uptake and level of blood activity (Figure 3A: y = -4.8551x + 5.2139; R2 = 0.6582). The largest deviation arises from 1. Injection of the radiotracer into the blood circulation exposes it to red blood cells (RBCs: most abundant cellular component) and albumin (most abundant protein component) prior to encountering cell membranes of the tissue or organ, in which tissue uptake and retention are a measure of physiology or pathology. Since the

99m

Tc radiotracer taken up by myocardium is free, its

availability for myocardial extraction depends largely on the extent to which the cellular and protein-bound radiotracer molecules become free during perfusion. The cellular and protein binding is the key factor controlling availability of 99mTc radiotracer for tissue uptake. Therefore, it is critical to evaluate the RBC and albumin-binding properties of new

99m

Tc(III) radiotracers.

In this study, blood samples were drawn from the animals injected with 1 – 3 and 8 – 11 at 2 min p.i. The cellular components were easily separated from blood plasma by centrifugation. The cellular components and supernatant were collected separately. The collected supernatant was allowed to pass through a membrane-based filter. The results from γ-counting of the collected solid, filter and filtrate show that 1 – 3, and 9 have 48 – 58% of total blood radioactivity binding to RBCs (Figure 3B) and only 2 – 3% binding to albumin. The remaining 39 – 49% of blood radioactivity is most likely free radiotracer in the filtrate. Radiotracers 8, 10 and 11 have 29 – 55% of blood radioactivity binding to RBCs, 5 – 15% to albumin, and 30 – 63% remaining free in blood plasma (Figure 3B). Radiotracers 1, 2, 3 and 9 all have little albumin binding (2 – 3% of the total blood radioactivity) and show high heart uptake (Figure 2: 3.3 – 5.4 %ID/g).

10


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Radiotracers 8, 10 and 11 have more albumin-binding (5 – 15% of the total blood radioactivity), and show relatively low heart uptake (Figure 2: 0.7 – 2.2 %ID/g). There is a regressive linear relationship between the 2-min radiotracer heart uptake and its % albumin-binding (Figure 3C: y = -0.2738x + 4.4609; R2 = 0.735). Impact of Boronate Caps. The biodistribution data (Table SI1) show that the boronate caps have a profound impact on biodistribution properties of new

99m

Tc radiotracers. For example, 1

and 9 are positional isomers and share almost the same lipophilicity as evidenced by their identical HPLC retention times (Table 1). Even though 1 and 9 share similar biodistribution patterns in normal organs (Table SI1), their heart uptake values are significantly different (5.38±0.19 %ID/g for 1 and 3.31±0.70 %ID/g for 9). Similar trend is also observed with 3 and 10. Replacing the benzene ring in 1 with a pyridine ring results in 2, which is less lipophilic (Table 1) due to the pyridine-N atom, and its 2-min heart uptake is lower than 1. Radiotracer 2 has more blood radioactivity than 1 (Table SI1). The liver uptake of 2 is lower than that of 1. Replacing the CH3 group in 1 and 9 with the CH3NH moiety leads to 3 and 10, both of which have lower heart uptake and more liver radioactivity than 1 and 9 (Table SI1). Radiotracer 4 is more lipophilic than 3 due to the extra N-CH3 moiety, and had higher liver uptake with lower heart uptake than 3 (Table SI1). Substitution of the CH3SO2 moiety in 1 with a (CH3)2NHSO2NH functional group leads to the formation of 8, which has more blood radioactivity (1.03±0.01 %ID/g) than 1 (0.33±0.04 %ID/g) because of the capability of 3DMSA moiety to bind to cellular and protein components in the blood (Figure 3). As a result, 8 shows lower heart uptake (0.72±0.03 %ID/g). Its liver uptake (2.36±0.42 %ID/g) is much lower than that of 1 (3.80±0.27 %ID/g).

11



A

B

Figure 4. A: Comparison of myocardial washout kinetics between 1, 2, 9 and 99mTc-Teboroxime. All experimental data are from biodistribution studies in SD rats (n = 3 – 4). B: Comparison of coronal views of SPECT images for the SD rats injected with 1, 2, 9 and 99mTc-Teboroxime, respectively, at 0 – 5, 5 – 10, 10 – 15, 15 – 20, 20 – 25, and 25 – 30 min p.i. These images are used to demonstrate the advantage of 1 and 2 over 99mTc-Teboroxime.

12


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Myocardial Washout Kinetics. Tables SI2 – SI4 list the biodistribution data for 1, 2 and 9, respectively. These three radiotracers are of our particular interest because of their high 2-min heart uptake (Figure 2). Figure 4A compares washout kinetics of 1, 2, 9 and

99m

Tc-Teboroxime

from the heart over the 60-min period. The curves are best fitted with the bi-exponential equation for 1 (y =1.03 + 2.27e-0.893X + 4.45e-0.067X: R2 = 0.9832), 2 (y = 0.95 + 1.47e-0.389X + 2.50e-0.029X: R2 = 0.9800), and 9 (y =1.11 + 1.27e-0.893X + 3.45e-0.067X: R2 = 0.9735). All three new radiotracers show the heart uptake higher than that for 99mTc-Teboroxime over the 60-min study period. The AUC values for 1 (AUC = 136), 2 (AUC = 120), and 9 (AUC = 92) are significantly higher than those reported for

99m

Tc-Teboroxime (AUC = 71).14 The AUC value of 1 is >2x of that for

99m

Tc-Teboroxime over the 60-min period. A larger AUC value indicates more radioactivity in

the heart during a specific period. As a result, it takes ~4 min for 2 and 9, and ~8 min for 1 to approach the heart uptake value of Since

99m

Tc-Teboroxime (Figure 4: ~3.0 %ID/g) at 2 min p.i.11

99m

Tc-Teboroxime has a linear relationship between its myocardial uptake and the blood

flow rate (0 – 5 mL/min/g) at 1 – 2 min p.i.,20 it is reasonable to believe the time window to maintain the same linear uptake/flow relationship will be 4 – 5 min for 2 and 9, and 8 – 10 min for 1, which should be long enough to acquire high quality heart images using both the standard and CZT-based SPECT cameras. Therefore, 1, 2 and 9 have significant advantages over

99m

Tc-

Teboroxime. This statement is further supported by the extremely promising results from SPECT studies (Figure 4B). Because of its fast myocardial washout,

99m

Tc-Teboroximine is only useful

for SPECT imaging at 0 – 5 min p.i. In contrast, high quality images are acquired during any of the 5-min window over the first 20 min after administration of 1 and 2. Since 9 has faster myocardial washout than 1 and 2 (Figure 4A), only the first 10 min is useful for high quality SPECT images with 9 (Figure SI3).

13



#

Page 14 of 36

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

* *

Figure 5. Direct comparison of organ uptake and heart/background ratios between 1, 2, 9 and Tc-Teboroxime. Biodistribution data for 99mTc-Teboroxime are obtained from our previous study.11 #: p < 0.05, significantly different from the value for 99mTc-Teboroxime. *: p < 0.01, significantly different from the value for 99mTc-Teboroxime. An optimal radiotracer should have lower uptake in blood, liver, lungs and muscle with the heart/background ratios better than those of 99mTc-Teboroxime. 99m

14


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Normal Organ Excretion Kinetics. Figure 5 compares the uptake values in background organs (blood, liver, lungs and muscle) and heart/background ratios for 1, 2, 9 and

99m

Tc-

Teboroxime. In general, 1, 2 and 9 have similar blood radioactivity levels (Figure 6: 0.33 – 0.45 %ID/g) with

99m

Tc-Teboroxime (0.49 %ID/g),14 but their heart/blood ratios were much better

because of their higher heart uptake. Radiotracers 1, 2 and 9 also had lower uptake in the lung and muscle. Their heart/lung and heart/muscle ratios are significantly (p < 0.05) higher than those of 99mTc-Teboroxime (Figure 5). Among the three new 99mTc(III) radiotracers evaluated in biodistribution studies, 1 has the highest heart uptake; but its heart/liver ratios are similar to those of 99mTc-Teboroxime. In contrast, 2 has the heart/liver ratios close to those of 99mTc-Teboroxime at 15 min p.i. because of its higher heart uptake and faster liver clearance kinetics. Radiotracer 2 has also shares very similar liver and lung uptake with 99m

Tc-PAboroxime;12 but its heart uptake (1.0 – 3.7 %ID/g) is higher than that for

99m

Tc-

PAboroxime (0.9 – 3.0 %ID/g) over the 60 min period.12 Radiotracer 2 exhibits the uptake values in the liver (0.9 – 3.8 %ID/g) and lungs (0.4 – 1.5 %ID/g) that are lower than those of

99m

Tc-

5Fboroxime (Liver: 2.5 – 4.5 %ID/g; Lung: 1.0 – 2.1 %ID/g) over the 60 min study period.14 Radiotracers 1, 2 and 9 all have low uptake in the fat (~0.3 %ID/g) and blood vessels (0.4 – 0.6 %ID/g) around the coronary arteries. This observation is consistent with the low radioactivity accumulation above the heart in the planar images (Figure SI2) for the SD rats administered with 1, 2 and 9, respectively. The high initial heart uptake (Figure 4) and high heart/background ratios (Figure 5) strongly suggest that 1, 2 and 9 are better radiotracers than SPECT MPI.

15


99m

Tc-Teboroxime for


Figure 6. SPECT and SPECT/CT images of the SD rats administered with 1 (n = 1), 2 (n = 3), 9 (n = 1) and 99mTc-Teboroxime (n = 1), respectively. SA = short axis; VLA = vertical long axis; HLA = horizontal long axis. These images were obtained at 0 – 5 min p.i. with the camera being focused in the heart region using a u-SPECT-II scanner. Anesthesia was induced using an air flow rate of 350 mL/min and ~3.0% isoflurane. 99mTc-Teboroxime is used only for comparison purpose. SPECT/CT images are used to illustrate the relative orientation and intensity of radioactivity in the heart region. Only one animal is used for each radiotracer. Radiotracer 2 has little interference from the liver radioactivity because of its low liver uptake. However, the liver radioactivity interference is significant in the 3D and VLA views of heart for SD rats administered with 1 and 9.

16


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SPECT Imaging. Figure 6 shows SPECT images of the SD rats at 0 – 5 min after administration of 1, 2 and 9 and

99m

Tc-Teboroxime, respectively, to demonstrate the superiority

of new 99mTc(III) radiotracers over 99mTc-Teboroxime. 99mTc-Teboroxime is used for comparison purposes. Radiotracer 2 shows the best image quality with lowest uptake in the liver, lungs and muscle. The interference from liver radioactivity is not significant (Figure 4) over the first 30min period. In contrast, 1 has more the liver radioactivity, which overlaps significantly with that in the heart at the bottom of inferior wall in the 3D and VLA (vertical long axis) images. Therefore, 2 has a significant advantage over 1 because of its low liver uptake and excellent heart/liver contrast. This conclusion is fully supported by the biodistribution data (Figure 5). It also has the advantage over

99m

Tc-PAboroxime and

99m

Tc-5Fboroxime reported in our previous

studies,12,14 due to its lower uptake in liver and lungs (Tables SI1 and SI3). SPECT Imaging in Pigs. Figure 8 shows the selected SPECT images of the pig (~25 Kg) administered with 2 (~ 75 MBq or ~2 mCi). The best imaging window is 0 – 5 min. Excellent heart images are also be acquired with 2 at 5 – 10 min p.i., during which it is impossible to acquire high quality SPECT images of the heart with

99m

Tc-Teboroxime (Figure 4B). Its liver

uptake increases steadily and peaks at ~15 min (Figure 8). The heart/liver ratio decreases rapidly during the first 10 min with the heart-to-liver ratios being 0.75 – 3.25. The average heart/liver ratio of 2 for the first 4 min is 2.15, which is close to that reported for

18

F-BMS747158 (2-t-

butyl-4-chloro-5-[4-(2-(18F)fluoroethoxymethyl)benzyloxy]-2H-pyridazin-3-1: heart/liver = 2.0 from PET quantification in pigs),21 and higher than that for

99m

Tc-Sestamibi (heart/liver =

1.0 over the first 6 – 7 min p.i.

18


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DISCUSSION MPI is a well-established non-invasive technique to measure the heart function and detect the perfusion defects.1-6

99m

Tc-Teboroxime is not an ideal perfusion radiotracer because of its fast

washout kinetics from the heart, which leads to reduction in the myocardial extraction fraction and loss of the uptake/flow linearity if the blood flow is >3.0 mL/m/g.3,20 As a result, its heart uptake significantly underestimates the changes in blood flow at 5.0 min after administration, which make it difficult to accurately track the regional blood flow rate.23-26 With tremendous developments in the CZT-based SPECT cameras,27-37 the nuclear cardiology community has been calling for better perfusion radiotracers with longer heart retention time and/or improved biodistribution properties.38-40 Development of such a radiotracer remains the key for future success of nuclear cardiology. The sulfonyl-containing boronate caps are useful for optimization of the heart uptake and pharmacokinetics of 99mTc radiotracers. Among the 99mTc radiotracers evaluated in SD rats, 1 has the initial heart uptake much higher than

99m

Tc-Teboroxime over the 60-min period (Figure 4).

Its initial heart uptake is also higher than that of

99m

Tc-PAboroxime and

99m

Tc-5Fboroxime

reported in our previous study.12,14 It takes ~8 min for 1 to reach the 2-min heart uptake value of 99m

Tc-Teboroxime (Figure 4: ~3.0 %ID/g). It is highly conceivable that the time window for 1 to

maintain the linear uptake/flow relationship is 8 – 10 min, which is much longer than that of 99m

Tc-Teboroxime (~2 min). However, its high liver uptake imposes significant challenge for its

clinical acceptance. Radiotracer 2 also has the higher heart uptake than that of 99mTc-Teboroxime over the 60-min period (Figure 4). It takes ~4 min for 2 to approach the 2-min heart uptake value of

99m

Tc-Teboroxime, suggesting that 2 may have a 4 – 5 min window to maintain the linear

uptake/flow relationship. Radiotracer 2 shares very similar lung uptake with 99mTc-PAboroxime;

19



Page 20 of 36

99m

Tc-PAboroxime

but its heart uptake (1.0 – 3.7 %ID/g) is higher as compared with those of (0.9 – 3.0 %ID/g) over the 60 min period.12 Radiotracer 2 and

99m

Tc-5Fboroxime share similar

heart uptake. However, the uptake values of 2 in the liver (0.9 – 3.8 %ID/g) and lungs (0.4 – 1.5 %ID/g) are lower than those of

99m

Tc-5Fboroxime (Liver: 2.5 – 4.5 %ID/g; Lung: 1.0 – 2.1

%ID/g) over the 60-min period.14 Radiotracer 2 shows the best image quality (Figures 6 and 8). Considering all these factors, we believe that 2 is a better radiotracer than 99mTc-Teboroxime and 1 for SPECT MPI. Why the heart uptake values from planar image quantification (Table 2) are so different from those from biodistribution (Tables SI1 – SI4)? The radioactivity from image quantification is accumulative over a specific period while the heart uptake from biodistribution is obtained at a specific point after radiotracer injection. The heart uptake values from planar images include parts of the radioactivity in blood-pool and normal organs. The heart uptake values can be readily corrected by deducting the radioactivity in normal organs. However, it is almost impossible to separate the blood-pool radioactivity from that in myocardium. This may explain why 1 and 8 shared similar AUC values (Table 2), despite the fact that the 2-min heart uptake value of 1 (5.38±0.19 %ID/g) is much higher than that of 8 (0.72±0.03 %ID/g). Another important question is why blood radioactivity has such an impact on the initial heart uptake of 99mTc radiotracers (Figure 3A). Radiotracer 2 has ~58% of the total blood radioactivity binding to RBCs, 2 – 3% binding to the albumin, and 39% remaining free in blood plasma (Figure 3B). Similar cellular binding properties were also observed with 1, 3, 8 and 9 (Figure 5). Even though the heart localization mechanism remains unknown for

99m

Tc(III) radiotracers

[99mTcCl(CDO)(CDOH)2B-R], one thing is certain that the RBC and albumin-binding plays a significant role in their biodistribution properties (Figure 3C). This conclusion is consistent with

20


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the results from studies on interactions between 99mTc-Teboroxime and RBCs.41 The results from this study also show that

99m

Tc radiotracers with more blood radioactivity have a lower heart

uptake. There is a regressive linear relationship between the 2-min heart uptake and blood radioactivity (Figure 3A) and % albumin-binding of

99m

Tc radiotracers (Figure 3C). The total

blood volume is 15 – 16 mL (16 – 18 g) for the SD rats of 200-g.15,20,43,43 In contrast, their hearts weigh only 0.65 – 0.70 g. As a result, small changes in blood radioactivity may result in a big difference in radiotracer availability for myocardial extraction. This may explain why low blood radioactivity is so important to maintain the high heart uptake of cardiac radiotracers. The next question is how the boronate caps influence biodistribution properties of complexes [99mTcCl(CDO)(CDOH)2B-R] (Figure 4). One possible explanation is related to the stability of the Tc-Cl bond. It was reported that complexes [99mTcCl(CDO)(CDOH)2B-R] are more stable when the R group contains two or more carbon atoms.15,16,44 More stable Tc-Cl bond makes it difficult for [99mTcCl(CDO)(CDOH)2B-R] to convert into the corresponding “hydroxide” complex [99mTc(OH)(CDO)(CDOH)2B-R], which has lower first-pass extraction and less heart uptake than [99mTcCl(CDO)(CDOH)2B-R].16 However, this hypothesis doesn’t explain the fact that radiotracers 1 and 9 share almost the same composition, and have so much difference in their heart uptake and myocardial retention time. The alternative explanation is most likely related to their capability for cellular and protein binding. This study clearly show that (1) the boronate caps have significant impact on the blood activity of [99mTcCl(CDO)(CDOH)2B-R] (Figure 3A), (2) radiotracers [99mTcCl(CDO)(CDOH)2B-R] bind to both RBCs and albumin (Figure 3B), and (3) there is a regressive linear relationship between the radiotracer heart uptake and % albumin-binding (Figure 3C). If the radiotracer [99mTcCl(CDO)(CDOH)2B-R] (e.g. 8) has a high RBC and albumin-binding capability, more radiotracer molecules will be blood-bound

21



Page 22 of 36

after injection. As a result, there will be less radioactivity for myocardial extraction and the radiotracer is expected to have low heart uptake. If the radiotracer [99mTcCl(CDO)(CDOH)2B-R] (e.g. radiotracer 2) has little RBC and albumin-binding, its blood radioactivity will be low, more radioactivity will be available for myocardial extraction, and the radiotracer will have high heart uptake. The liver uptake of 2 is close to that of

99m

Tc-Teboroxime (Figure 3). Its liver radioactivity

peaks at ~15 min in pigs (Figure 8). The heart/liver ratio over the first 4 min is close to that of 18

F-BMS747158,21 and higher than that for 99mTc-Sestamibi.22 High initial heart uptake and high

heart/liver ratios are important because dynamic imaging is often performed for quantification of blood flow during the first 5 min p.i.21,22 Due to tremendous improvement in spatial resolution and sensitivity for CZT-based SPECT cameras (such as D-SPECT and the Discovery NM 530c),27-37 it is possible to complete a SPECT scan in 2 – 5 min using only 4 – 5 mCi of

99m

Tc

radiotracer. The use of D-SPECT also makes it easier to minimize the overlap between the heart and liver radioactivity because the patient is placed at the upright position, and liver tends to drop more downward than heart. CONCLUSIONS Among the new

99m

Tc(III) radiotracers evaluated in SD rats, 2 shows the most promising

characteristics of a heart imaging agent. Its initial heart uptake is well comparable to that of 99m

Tc-Teboroxime, but its heart retention time is significantly longer. The heart/blood, heart/lung

and heart/muscle ratios of 2 are much higher than those of 99mTc-Teboroxime. The SPECT image quality with 2 is much better than that with

99m

Tc-Teboroxime at 0 – 5 min p.i. The high initial

heart uptake, long myocardial retention and high heart/background ratios make 2 an excellent candidate for future translation in clinics.

22


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EXPERIMENTAL METHODS Materials. Chemicals (citric acid, γ-cyclodextrin, cyclohexanedione dioxime (CDOH2), diethylenetriaminepentaacetic

acid

boronic acid (3DMSA-B(OH)2),

(DTPA),

3-(N,N-dimethylaminosulfonyl)aminophenyl-

3-(N,N-dimethylsulfamoyl)phenylboronic acid (3DMS-

B(OH)2), 4-methoxy-3-(morpholinosulfonyl)phenylboronic acid (3MMS-B(OH)2), 3-(methylsulfonyl)aminobenzeneboronic acid (3MSA-B(OH)2), 3-[(methylamino)sulfonyl]benzeneboronic acid (3MS-B(OH)2), 4-[(methylamino)sulfonyl]benzeneboronic acid (4MS-B(OH)2), 3-(methylsulfonyl)phenylboronic acid (3S-B(OH)2), 4-(methylsulfonyl)phenylboronic acid (4S-B(OH)2), 3-(methylsulfonyl)pyridineboronic acid (3SP-B(OH)2), (3-(N-methyl-sulfamoyl))phenyl)boronic acid

(3MS-B(OH)2),

3-(morpholinosulfonyl)phenylboronic

acid

(3MSB-B(OH)2),

4-

(morpholinosulfonyl)phenylboronic acid (4MSB-B(OH)2), sodium chloride and SnCl2.2H2O) were purchased from Sigma/Aldrich (St. Louis, MO) or Matrix Scientific (Columbia, SC). Na99mTcO4 were obtained from Cardinal HealthCare® (Chicago, IL). Radio-HPLC Method. The radio-HPLC method for analysis of

99m

Tc radiotracers used an

Agilent HP-1100 HPLC system (Agilent Technologies, Santa Clara, CA) equipped with a β-ram IN/US detector (Tampa, FL) and Zorbax C8 column (4.6 mm x 250 mm, 300 Å pore size; Agilent Technologies, Santa Clara, CA). The flow rate was 1 mL/min. The mobile phase was isocratic with 30% solvent A (10 mM NH4OAc buffer, pH = 6.8) and 70% solvent B (methanol) between 0 and 5 min, followed by a gradient from 70% solvent B at 5 min to and 90% solvent B at 15 min, and isocratic mobile phase with 10% solvent A and 90% solvent B. The RCP was reported as the percentage of area for the expected radiometric peak on each radio-HPLC chromatogram of each 99mTc(III) radiotracer.

23



Radiosynthesis and Solution Stability. Radiotracers [99mTcCl(CDO)(CDOH)2B-R] were prepared using the kit formulation.11-14 Each vial contains 2 mg of CDOH2, 4 – 5 mg of boronic acid, 50 – 60 µg of SnCl2·2H2O, 9 mg of citric acid, 2 mg of DTPA, 50 mg of NaCl and 20 mg of γ-cyclodextrin. To a lyophilized vial was added 1.0 mL 99mTcO4- solution (370 – 1110 MBq). The vial was heated at 100 oC for ~10 min. A sample of the resulting solution was diluted with saline containing ~20% propylene glycol to 3.7 MBq/mL. The diluted solution was analyzed by radio-HPLC and ITLC. The RCP was 95 – 98% with minimal [99mTc]colloid (24 h. Animals were anesthetized with intramuscular injection of a mixture of ketamine (80 mg/kg) and xylazine (19 mg/kg) before being used for biodistribution and planar imaging studies.

24


Page 24 of 36

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Protocol for Dynamic Imaging in SD Rats. Dynamic imaging was performed in SD rats (n = 5: 200 – 250 g). Each animal was administered with the

99m

Tc radiotracer (40 – 75 MBq).

After injection, the animal was immediately (within 5 – 10 seconds) placed prone on a single head mini γ-camera (Diagnostic Services Inc., NJ). Planar images were acquired every 30 seconds during first 5 min, followed by images every 2 min at 6 – 30, 40, 50 and 60 min p.i. The imaging data were stored digitally in a 128 x 128 matrix. After planar imaging, the animals were returned to a lead-shielded cage. Planar images were analyzed by drawing regions of the heart (heart radioactivity) and whole body (injected radioactivity). The background was corrected by drawing the region right above heart. The results were expressed as the percentage of injected radioactivity (%ID). The myocardial washout kinetics was determined by curve fitting with GraphPad Prism 5.0 (GraphPad Software, Inc., San Diego, CA). The data were reported as an average ± standard deviation. Comparison between two radiotracers was made using a one-way ANOVA test. The level of significance was set at p < 0.05. Biodistribution Protocol. Fifteen SD rats (200 – 250 g) were divided randomly into five groups. Each animal was administered with 100 – 111 KBq of 99mTc radiotracer via the tail-vein injection. Three animals were sacrificed by sodium pentobarbital overdose (100 – 200 mg/kg) at 2, 5, 15, 30 and 60 min p.i. Blood was withdrawn from heart. Organs of interest (heart, brain, fat, intestines, kidneys, liver, lungs, muscle, spleen and vessels around the artery) were harvested, rinsed with saline, dried with absorbent tissues, weighed and counted on a Perkin Elmer Wizard – 1480 γ-counter (Shelton, CT). The organ uptake was reported as the percentage of injected dose (% ID) or percentage of injected dose per gram of organ tissue (%ID/g) from three SD rats in each group. Comparison between two

99m

Tc radiotracers was made using one-way ANOVA

test (GraphPad Prism 5.0, San Diego, CA). The level of significance was set at p < 0.05.

25



Cellular and Protein-Binding Assay. Blood samples were withdrawn (0.5 – 1.0 mL) from the heart at 2 min p.i. and were centrifuged at 12,000 rpm (Microfuge 22R Centrifuge, Beckman Coulter, Indianapolis, IN) for 10 – 15 min. The solid (mainly RBCs) and supernatant were collected and countered on a Perkin Elmer Wizard – 1480 γ-counter (Shelton, CT). The percentage of RBC-binding was calculated as percentage of the total blood radioactivity. Protein binding of

99m

Tc radiotracers was evaluated by ultrafiltration according to literature method.45

Each Amicon Centrifree® (Beverly, MA) ultrafiltration device (30,000 Dalton NMWL) was loaded with 300 – 600 µL of the collected blood plasma above. The Centrifree® devices were immediately centrifuged at 12,000 rpm for 25 – 30 min. The filter and collected filtrate were countered on a γ-counter. The

99m

Tc radioactivity on the filter represents the percentage of

protein-binding, and that in the filtrate indicates the percentage of free 99mTc radiotracer. SPECT Imaging Protocol in SD Rats. SPECT imaging was performed the u-SPECT-II/CT scanner (Milabs, Utrecht, The Netherlands) equipped with a 1.0 mm multi-pinhole collimator. The SD rat was placed into a shielded chamber connected to an isoflurane anesthesia unit (Univentor, Zejtun, Malta). Anesthesia was induced using an air flow rate of 350 mL/min and ~3.0% isoflurane, and maintained using an air flow of ~250 mL/min with ~2.5% isoflurane during image data acquisition (6 frames: 75 projections over 5 min per frame). The animal was administered with the

99m

Tc radiotracer (120 – 150 MBq) in 0.5 mL saline containing ~20%

propylene glycol by tail vein injection. Rectangular scan in regions of interest (ROIs) from SPECT and CT were selected one the basis of orthogonal X-ray images provided by the CT. After SPECT acquisition, the animal was allowed to recover in a shielded cage. Image Reconstruction and Data Processing. SPECT reconstruction was performed using a POSEM (pixelated ordered subsets by expectation maximization) algorithm with 6 iterations and

26


Page 26 of 36

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16 subsets. CT data were reconstructed using a cone-beam filtered back-projection algorithm (NRecon v1.6.3, Skyscan). After reconstruction, the SPECT and CT data were automatically coregistered according to the movement of the robotic stage, and re-sampled to equivalent voxel sizes. Co-registered images were further rendered and visualized using the PMOD software (PMOD Technologies, Zurich, Switzerland). A 3D-Guassian filter (1.2 mm FWHM) was applied to smooth noise, and the LUTs (look up tables) were adjusted for good visual contrast. The images were visualized as both orthogonal slices and maximum intensity projections. SPECT Imaging Protocol in Pigs. SPECT studies were performed on 1 and 2 in normal pigs (23 – 26 Kg). The imaging protocol was approved by the Fu Wai Hospital Animal Care and Use Committee (Beijing, China). The rest SPECT scan was acquired in list mode data format on a Discovery NM 530c CZT SPECT camera (GE, USA) and followed by a CT scan on a GE Discovery 640 SPECT/CT camera. The animal was anesthetized with intravascular injection of 3% pentobarbital sodium (30 mg/kg). Additional sodium pentobarbital were used, when needed. The animal was maintained with mechanical ventilation, monitored with electrocardiogram (ECG), and kept in the same position. Each animal was injected with ~75 MBq of

99m

Tc

radiotracer without saline flushing. List mode acquisitions were immediately started and continued for 30 min. The image data were processed to create dynamic raw data (6 frames; 5 min per frame) and reconstructed with a SPECT dedicated processing software, MyoFlowQ (BCBTI, Taiwan). Quantitative dynamic images were then analyzed to measure heart-liver ratio with Image J 1.49 (the National Institutes of Health, United States). Data and Statistical Analysis. Biodistribution data, T/B ratios and imaging quantification data were reported as an average ± standard deviation based on the results from four to six SD

27



Page 28 of 36

rats at each time point. Comparison between two radiotracers was made using a one-way ANOVA test. The level of significance was set at p < 0.05. Supporting Information Available: The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxxxxxx. Molecular formula strings are not available for all new radiotracers. Tables listing biodistribution data for new 99mTc(III) radiotracers; Figures showing HPLC chromatograms, planar images, and SPECT images. (PDF) AUTHOR INFORMATION Corresponding Authors *W.F. e-mail: [email protected]. *S.L. e-mail: [email protected]. Conflict of interest: The authors declare no competing financial interest. Acknowledgement. Authors would thank Dr. Andy Schaber for his assistance in SPECT studies. This work was supported by Purdue University, the research grant R21 EB017237-01 (S.L.) from the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and grant 81771872 from the National Nature Science Foundation of China (YZ). ABBREVIATIONS General Terms: AUC: area under curve; CAD: coronary artery disease; CT: computed tomography; CZT: cadmium-zinc-telluride; DTPA: diethylenetriaminepentaacetic acid; ITLC: instant thin layer chromatography; MPI: myocardial perfusion imaging; RCP: radiochemical purity; and SPECT: single photon-emission computed tomography. Known

Radiotracers:

18

F-BMS747158-02:

(18F)fluoroethoxymethyl)benzyloxy]-2H-pyridazin-3-1;

28


2-tert-butyl-4-chloro-5-[4-(299m

Tc-Teboroxime:

Page 29 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


[99mTcCl(CDO)(CDOH)2B-CH3] (CDOH2 = cyclohexanedione dioxime); [99mTcCl(CDO)(CDOH)2B-PA]

(PA

=

Tc-PAboroxime:

99m

1H-pyrazol-3-yl);

[99mTcCl(CDO)(CDOH)2B-5F] (5F = 2-formylfuran-5-yl);

99m

Tc-5Fboroxime:

99m

TcN-NOET: [99mTcN(NOET)2]

(NOET = N-ethoxy,N-ethyl(dithiocarbamato); and 99mTc-Sestamibi: [99mTc(MIBI)6]+ (MIBI = 2methoxy-2-methylpropylisonitrile). New

99m

Tc-3Sboroxime

Radiotracers:

(methylsulfonyl)phenyl);

[99mTcCl(CDO)(CDOH)2B-3S]

(1):

99m

Tc-3SPboroxime (2): [

(methylsulfonyl)pyridin-3yl);

Tc-3MSboroxime (3): [99mTcCl(CDO)(CDOH)2B-3MS] (3MS

[99mTcCl(CDO)(CDOH)2B-3MSB]

99m

Tc-3DMSboroxime (4): [99mTcCl(CDO)(CDOH)2B-

(3MSA

=

(3MSB

=

99m

Tc-3MSBboroxime (5):

3-(morpholinosulfonyl)phenyl);

[99mTcCl(CDO)(CDOH)2B-3MMS]

(morpholinosulfonyl)phenyl);

3-

TcCl(CDO)(CDOH)2B-3SP] (3SP = 5-

3DMS] (3DMS = 3-(N,N-dimethylaminosulfonyl)aminophenyl);

(6):

=

99m

= 3-[(methylamino)sulfonyl]phenyl);

3MMSboroxime

(3S

99m

99m

Tc-3MSAboroxime (7):

[

3-(methylsulfonyl)aminophenyl);

(3MMS

=

99m

Tc-

4-methoxy-3-

99m

TcCl(CDO)(CDOH)2B-3MSA]

99m

Tc-3DMSAboroxime

(8):

[99mTcCl(CDO)(CDOH)2B-3DMSA] (3DMSA = 3-(N,N-dimethylaminosulfonyl)aminophenyl); 99m

Tc-4Sboroxime (9): [99mTcCl(CDO)(CDOH)2B-4S] (4S = 4-(methylsulfonyl)phenyl);

99m

Tc-

4MSboroxime (10): [99mTcCl(CDO)(CDOH)2B-4MS] (4MS = 4-[(methylamino)sulfonyl]phenyl); and

99m

Tc-4MSBboroxime (11): [99mTcCl(CDO)(CDOH)2B-4MSB] (4-MSB = 3-

(morpholinosulfonyl)phenyl).

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