Radiotracer For Myocardial Perfusion Imaging Research Articles

Radioiodinated Procainamide as Radiotracer for Myocardial Perfusion Imaging in Mice

Radioiodinated Procainamide as Radiotracer for Myocardial Perfusion Imaging in Mice

Technetium-99m Radiopharmaceuticals for Ideal Myocardial Perfusion Imaging: Lost and Found Opportunities.

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [99mTc]Tc-Sestamibi, [99mTc]Tc-Tetrofosmin, and [99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [99mTc]Tc-Sestamibi and [99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in 99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies.

Radioiodinated Azilsartan as a New Highly Selective Radiotracer for Myocardial Perfusion Imaging

Radioiodinated Azilsartan as a New Highly Selective Radiotracer for Myocardial Perfusion Imaging

Radiosynthesis, chromatographic evaluation and biodistribution of [125I]iododobutamine as a radiotracer for myocardial perfusion imaging

The objective of this work was to develop a potential selective radiotracer for the non-invasive assessment of heart imaging. [125I]iododobutamine was obtained via direct electrophilic substitution reaction with a high labeling yield of 96.79 ± 0.86%. The in vivo biodistribution of iodinated dobutamine showed high heart uptake of 31.49 ± 1.3%ID/g at 2 min after injection with low lungs and liver consumption which alleviate rapid myocardial imaging with significant minimum radiation hazards risk to the patients. Receptor blocking study showed reduction of heart uptake to 0.9 ± 0.01% which confirm the selectivity and specificity of [125I]iododobutamine for beta-adrenoceptors.

New 99mTc Radiotracers for Myocardial Perfusion Imaging by SPECT.

Myocardial Perfusion Imaging (MPI) with radiotracers is an integral component in evaluation of the patients with known or suspected coronary artery diseases (CAD). 99mTc-Sestamibi and 99mTc-Tetrofosmin are commercial radiopharmaceuticals for MPI by single photon-emission computed tomography (SPECT). Despite their widespread clinical applications, they do not meet the requirements of an ideal perfusion imaging agent due to their inability to linearly track the regional myocardial blood flow rate at >2.5 mL/min/g. With tremendous development of CZT-based SPECT cameras over the past several years, the nuclear cardiology community has been calling for better perfusion radiotracers with improved extraction and biodistribution properties. This review will summarize recent research efforts on new cationic and neutral 99mTc radiotracers for SPECT MPI. The goal of these efforts is to develop a 99mTc radiotracer that can be used to detect perfusion defects at rest or under stress, determine the regional myocardial blood flow, and measure the perfusion and left ventricular function. The advantage of cationic radiotracers (e.g. 99mTc-Sestamibi) is their long myocardial retention because of the positive molecular charge and fast liver clearance kinetics. 99mTc-Teboroxime derivatives have a high initial heart uptake (high first-pass extraction fraction) due to their neutrality. 99mTc- 3SPboroxime is the most promising radiotracer for future clinical translation considering its initial heart uptake, myocardial retention time, liver clearance kinetics, heart/liver ratios and SPECT image quality. 99mTc-3SPboroximine is an excellent example of perfusion radiotracers, the heart uptake of which is largely relies on the regional blood flow. It is possible to use 99mTc-3SPboroximine for detection of perfusion defect(s), accurate quantification and determination of regional blood flow rate. Development of such a 99mTc radiotracer is of great clinical benefit for accurate diagnosis of CAD and assessing the risk of future hard events (e.g. heart attack and sudden death) in cardiac patients.

Radioiodinated esmolol as a highly selective radiotracer for myocardial perfusion imaging: In silico study and preclinical evaluation

Challenges facing cardiovascular imaging necessitate innovation of better radiopharmaceuticals to augment or replace the existing ones. This research assesses the ability and competency of radioiodinated esmolol as a potential cardio selective imaging agent. Radioiodinated esmolol was synthesized with 97.3 ± 0.3% radiochemical yield and with high stability up to 48 h at room temperature as well as in rat serum. Molecular modeling study was performed to confirm the binding of iodinated esmolol to β1-adrenergic receptor. Its biodistribution studies in normal Swiss albino mice showed high heart uptake (38.5 ± 0.11%ID/g at 5 min p.i.), heart/liver ratio nearly 3.85:1 and heart/lungs ratio was about 7:1 at 5 min p.i. The evidenced selectivity of the radioiodinated esmolol to β1-adrenoceptor was confirmed by prior injection of cold esmolol. Gamma camera biodistribution pattern showed that radioiodinated esmolol accumulated selectively in heart.

Novel 99mTc(III) Complexes [99mTcCl(CDO)(CDOH)2B-R] (CDOH2 = Cyclohexanedione Dioxime) Useful as Radiotracers for Heart Imaging.

In this study, we evaluated seven new 99mTc(III) complexes [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-methoxypyridin-3-yl (MPY); 99mTc-PMboroxime: R = 1,5-pyrimidin-3-yl (PM); and 99mTc-4PYboroxime: R = pyridin-4-yl (4PY)) for their potential as heart imaging agents. All new 99mTc(III) 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 performed in SD rats. Planar image quantification was performed to compare their myocardial retention times. We found that the myocardial washout curves of new 99mTc(III) radiotracers were best fitted the biexponential decay function. The AUC (area under the curve) 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) > 99mTc-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) compared well to the 2 min heart uptake of 99mTc-Teboroxime (3.00 ± 0.37%ID/g). It took ∼5 min for 99mTc-5Fboroxime to approach the 1 min heart uptake value of 99mTc-Teboroxime (∼3.5% ID/g) and ∼9.5 min to reach the 2 min heart uptake value of 99mTc-Teboroxime (∼3.0% ID/g). The best image acquisition window is 0-5 min for 99mTc-5Fboroxime. High-quality single-photon emission computed tomography images of the rat hearts were acquired in any of the 5 min window over the first 20 min after its administration. 99mTc-5Fboroxime has significant advantages over 99mTc-Teboroxime as the radiotracer for myocardial perfusion imaging.

Radioiodinated acebutolol as a new highly selective radiotracer for myocardial perfusion imaging.

Acebutolol was successfully labeled with (125) I via direct electrophilic substitution reaction. Radioiodinated acebutolol was prepared with a maximum radiochemical yield of 96.5 ± 0.3% and in vitro stability up to 72 h. The in vivo biological distribution of radioiodinated acebutolol showed high heart uptake of 37.8 ± 0.14% injected activity/g organ with low lungs and liver uptakes at 5 min post-injection. In vivo receptor blocking study was carried out in mice to evaluate its selectivity to heart. Radioiodinated acebutolol showed fast heart accumulation with high heart/liver ratio, which provides the ability for fast myocardial imaging with significant decrease in the radiation hazards risk on patients. So, radioiodinated acebutolol could be displayed as a radiotracer drug of choice in case of emergency patients for myocardial perfusion imaging.

Development of kit formulations for (99m) TcN-MPO: a cationic radiotracer for myocardial perfusion imaging.

The objective of this study was to develop a kit formulation for [(99m) TcN(mpo)(PNP5)](+) (MPO = 2-mercaptopyridine oxide), ((99m) TcN-MPO) to support its clinical evaluations as a SPECT radiotracer. Radiolabeling studies were performed using three different formulations (two-vial formulation and single-vial formulations with/without SnCl2 ) to explore the factors influencing radiochemical purity (RCP) of (99m) TcN-MPO. We found that the most important factor affecting the RCP of (99m) TcN-MPO was the purity of PNP5. (99m) TcN-MPO was prepared >98% RCP (n = 20) using the two-vial formulation. For single-vial formulations with/without SnCl2 , β-cyclodextrin (β-CD) is particularly useful as a stabilizer for PNP5. The RCP of (99m) TcN-MPO was 95-98% using β-CD, but its RCP was only 90-93% with γ-cyclodextrin (γ-CD). It seems that PNP5 fits better into the inner cavity of β-CD, which forms more stable inclusion complex than γ-CD in the single-vial formulations. The results from biodistribution and imaging studies in Sprague-Dawley rats clearly demonstrated biological equivalence of three different formulations. Single photon-emission computed tomography data suggested that high quality images could be obtained at 0-30-min post-injection without significant interference from the liver radioactivity. Considering the ease for (99m) Tc-labeling and high RCP of (99m) TcN-MPO, the non-SnCl2 single-vial formulation is an attractive choice for future clinical studies.

Toxicological Evaluation of a Rotenone Derivative in Rodents for Clinical Myocardial Perfusion Imaging

Myocardial perfusion scintigraphy is a valuable clinical tool for assessing coronary blood flow deficits in patients. We recently synthesized a new iodinated compound (123I-CMICE-013) based on rotenone and showed that it has excellent performance as a radiotracer for myocardial perfusion imaging. Here, we describe the cellular toxicity and subacute toxicity of CMICE-013 in rats. Cultured hepatocytes displayed sensitivity to rotenone but not CMICE-013 at equimolar concentrations. Following i.v. injection of CMICE-013 for 14 days, body weight, ambulation, behavior, grooming, guarding (abdominal, muscular), pale conjunctivae, and food intake were observed. Biochemical, hematological, and histopathological changes in tissues (heart, liver, kidney, spleen, lung, and brain) and echocardiography at pre- and post-dosing were also examined. All animals responded well to the daily injections of CMICE-013 and showed no mortality or adverse reactions with respect to the parameters above. Subacute i.v. injections at high- (5 μg/kg) and low (1 μg/kg)-dose levels did not result in any significant changes to either biochemical or hematological parameters and no detectable changes in histopathology compared to the vehicle or untreated animals. Echocardiographic analyses, including the measurements of cardiac function and anatomy (wall thickness, left atrial size, and left ventricular mass), were not different at pre- versus post-dose measures and were not different compared to the vehicle or untreated animals. Our observations in small animals reveal that CMICE-013 induces minimal toxicity when delivered intravenously for 14 days.

Lessons From the Tc-99m Shortage

Background— In 2009, the Chalk River nuclear reactor closed for repairs that led to a critical shortage of technetium-99m (Tc-99m). Several centers used thallium-201 (Tl-201) as an alternative radiotracer for myocardial perfusion imaging. Because Tl-201 is considered by many as a suboptimal radiotracer, we sought to understand the impact of using Tl-201 (during the Tc-99m shortage) on downstream resource utilization. Methods and Results— We performed a retrospective study at the Ottawa Heart Institute of 7402 patients (60% men; mean age, 62.6±11.8 years), patients were referred for myocardial perfusion imaging between May 2008 and January 2011 (PRE_Tc-99m [2938 patients]), during (DURING_Tl-201 [2959 patients]), and after (POST_Tc-99m [1505 patients]) the Tc-99m shortage. Patients were followed for 6 months after their index myocardial perfusion imaging to determine subsequent rates of cardiac catheterization or noninvasive imaging. More downstream testing was seen in the Tl-201 cohort (639 [21.4%] patients) than the Tc-99m cohort (537 [12.1%] patients; P <0.001). After adjustment using propensity scores, differences in downstream referral rates were maintained. The downstream investigations resulted in an estimated increase in per-patient costs ($165.22; 95% confidence interval, 153.00–177.42) in the DURING_Tl-201 cohort compared with the Tc-99m cohort ($90.97; 95% confidence interval, 83.42–98.90; P <0.001). As well, the mean effective radiation dose per-patient was higher in DURING_Tl-201 (23.57 mSv; 95% confidence interval, 23.16–23.96) than in Tc-99m (12.92 mSv; 95% confidence interval, 12.55–13.40; P <0.001). Conclusions— In this single-center study, the use of Tl-201 during the Tc-99m shortage was associated with an increase in downstream testing, cost, and patient radiation exposure, but these findings may not be generalizable to other centers. Although Tl-201 provided a short-term solution to the unexpected Tc-99m shortage, long-term cost-effective solutions should be areas of future study.

Development of Radiolabeled Compounds for Myocardial Perfusion Imaging

Coronary artery disease (CAD) is the main cause of death and remains a major health problem worldwide. Myocardial perfusion imaging is a well established noninvasive method for assessing CAD. This review summarizes the development of various radiotracers for myocardial perfusion imaging, including single photon emission computed tomography (SPECT) perfusion imaging agents and positron emission tomography (PET) perfusion imaging agents and introduces novel basic research data related to this area. In addition, the current state of the art in myocardial perfusion imaging agents and the future direction are discussed in this review.

A comparative study of 99 Tc m N-mercaptopyridine-N-oxide and 99 Tc m -sestamibi myocardial perfusion imaging on acute myocardial infarction canine model

Objective The purpose of the present study is to compare the pharmacokinetic and biodistribution properties of 99Tcm N-mercaptopyridine-N-oxide (99 Tcm N-MPO) with 99 Tcm-sestamibi (99 Tcm-MIBI) in normal dogs, and to investigate the potential of 99TcmN-MPO as a myocardial perfusion agent in canines with acute myocardial infarction. Methods Twelve healthy mongrel dogs were injected intravenously with 99TcmN-MPO (n = 6) or 99Tcm-MIBI (n = 6). Tracer kinetics in body fluids were determined by collecting blood of 1 ml via a femoral vein catheter at 30 s, 1,2,3,4,5, 10, 20, 30, 40, 60and 90 min post-injection (p. i.). The collected blood samples were weighed and counted for radioactivity in a γ-counter. Anterior and posterior planar γ-camera images were collected at 10, 20, 30, 60, 90, and 120 min after injection, with organ uptake quantified by region-of-interest (ROIs) analysis. For comparison, 99Tcm-MIBI was also evaluated in the same twelve dogs. Canine infarct models were set up by micro-invasive interventional embolization. SPECT images in the canine infarct model were collected 24 hours after myocardial infarction at 30 min and 60 min after the administration of 99Tcm N-MPO (n = 5) or 99Tcm-MIBI (n = 5). Results Both of 99Tcm N-MPO and 99Tcm-M1BI had a rapid blood clearance with less than 50% of initial radioactivity remaining at 1 min [99TcmN-MPO: (35. 77 ± 6. 31)% ID/mg ,99Tcm-MIBI (34. 46 ± 6. 83) % ID/mg] and less than 5% at 30 min p. i. [99Tcm N-MPO(3. 11 ± 1.44) % ID/mg,99Tcm-MIBI (2.93 ±0. 39)% ID/mg] . After injection, 99TcmN-MPO showed significant accumulation in the myocardium and prolonged retention. This rapid liver clearance of 99TcmN-MPO led to favorable heart-to-liver ratios, reaching values of 0. 54 ±0. 06 at 10 min, 1.02 ±0. 06 at 30 min, and 1.38 ±0. 06 at 60 min p. i.In contrast, the heart/liver ratio of 99Tcm-MIBI remained low at all time points (0. 46 ± 0. 03 at 10 min,0. 63 ±0. 03 at 30 min, and 0. 62 ± 0. 12 at 60 min p. i.). SPECT imaging studies in canines with acute myocardial infarction indicated that good visualization of the left ventricular wall and perfusion defects could be achieved at 30 min after administration of 99TcmN-MPO, but not 99Tcm-MIBI. Conclusion The combination of high heart uptake and rapid liver clearance makes 99TcmN-MPO a promising new radiotracer for myocardial perfusion imaging. Key words: Myocardial infarction; Radioisotopes; Tomography, emission-computed,singlephoton

025 Validation of a “low dose thallium 201 protocol” with a cadmium-zinc-telluride (CZT) cardiac camera

Thallium 201 is the most efficient radiotracer for myocardial perfusion imaging but leads to relative high radiation exposure for patients. We used a new cardiac CZT camera to decrease the effective dose with thallium-201 in myocardial perfusion imaging. We prospectively studied 137 consecutive patients referred for stress myocardial perfusion imaging and who previously had in the last 5 years a myocardial SPECT with thallium-201. We injected at stress a low dose of thallium 201 (1 to 1.2 MBq/kg, i.e. 74 MBq for 70 kgs), performed stress myocardial imaging in 5 to 7 mn with a CZT camera GE Discovery NM 530c and redistribution imaging when initial images were abnormal, with reinjection (37 MBq) when previous myocardial infarction or severe defect or without reinjection in other cases. We compared the CZT scan with the scan previously performed in the last 5 years with conventional dual head tomographic Anger camera (CC) with a regular dose of thallium-201. Patients had known coronary artery diseases in 85% of cases, myocardial scar in 38% and ischemia in 20%. The average stress dose was 88 MBq versus 125 MBq previously (−30%) The average time for camera acquisition was 6 mn versus 13 mn (−54%) The cardiac counts statistic was higher with CZT (>1 Mcts) By comparison with CC, the quality of CZT images was better (better delineation of left ventricular cavity, visualization of papillary muscles, easier thickening analysis) in 70% of cases, equal in 24% and worse in 6% (6 artefacts, 2 digestive contaminations) Comparison of artefacts showed 30 unmodified, 29 less and 6 additionnal artefacts. By comparison with the previous SPECT, we missed no pathological image; furthermore, we detected 5 true pathological images which were missed with the CC. Calculated effective dose was less than 12 mSv when no reinjection and less than 18 mSv when reinjection. With reduced activities of thallium 201 (−30%) and effective doses between 12 and 18 mSv, CZT camera gives reliable high quality imaging

Evaluation of 99 mTcN-MPO as a New Myocardial Perfusion Imaging Agent in Normal Dogs and in an Acute Myocardial Infarction Canine Model: Comparison with 99 mTc-Sestamibi

(99) (m)TcN-MPO ([(99) (m)TcN(mpo)(PNP5)](+): mpo = 2-mercaptopyridine oxide and PNP5 = N-ethoxyethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]amine) is a cationic (99) (m)Tc-nitrido complex, which has favorable biodistribution and myocardial uptake with rapid liver clearance in Sprague Dawley rats. The objective of this study was to compare the biodistribution and pharmacokinetics of (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi in normal dogs, and to evaluate the potential of (99) (m)TcN-MPO as a myocardial perfusion agent in canines with acute myocardial infarction. Five normal mongrel dogs were injected intravenously with (99) (m)TcN-MPO. Venous blood samples were collected via a femoral vein catheter at 0.5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 60, and 90 min post-injection (p.i.). Anterior-posterior planar images were acquired by γ-camera at 10, 20, 30, 60, 90, and 120 min p.i. Regions of interest (ROIs) were drawn around the heart, liver, and lungs. The heart/liver and heart/lung ratios were calculated by dividing the mean counts in heart ROI by the mean counts in the liver and lung ROI, respectively. For comparison, (99) (m)Tc-sestamibi was also evaluated in the same five dogs. The interval period between the two examinations was 1 week to eliminate possible interference between these two radiotracers. In addition, single positron emission computed tomography (SPECT) images in the canine infarct model were collected 24 h after myocardial infarction at 30 and 60 min after the administration of (99) (m)TcN-MPO (n = 4) or (99) (m)Tc-Sestamibi (n = 4). It was found that (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi displayed very similar blood clearance characteristics during the first 90 min p.i. Both (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi had a rapid blood clearance with less than 50% of initial radioactivity remaining at 1 min and less than 5% at 30 min p.i. (99) (m)TcN-MPO and (99) (m)Tc-Sestamibi both showed good heart/lung contrast. The heart/liver ratio of (99) (m)TcN-MPO increased with time (0.53 ± 0.06 at 10 min, 0.90 ± 0.062 at 30 min, and 1.22 ± 0.06 at 60 min p.i.), whereas the heart/liver ratio of (99) (m)Tc-Sestamibi remained low at all time points (0.50 ± 0.03 at 10 min, 0.64 ± 0.03 at 30 min, and 0.60 ± 0.02 at 60 min p.i.). SPECT imaging studies in canines with acute myocardial infarction indicated that good visualization of the left ventricular wall and perfusion defects could be achieved at 30 min after administration of (99) (m)TcN-MPO but not after (99) (m)Tc-Sestamibi. The combination of reasonable heart uptake with rapid hepatobiliary excretion makes (99) (m)TcN-MPO a promising new radiotracer for myocardial perfusion imaging.

Biological in Vitro and in Vivo Studies of a Series of New Asymmetrical Cationic [99mTc(N)(DTC-Ln)(PNP)]+ Complex (DTC-Ln = Alicyclic Dithiocarbamate and PNP = Diphosphinoamine)

(99m)Tc(N)-DBODC5 is a cationic mixed compound under clinical investigation as potential myocardial imaging agent. In spite of this, analogously to the other cationic (99m)Tc-agents, presents a relatively low first-pass extraction. Thus, modification of (99m)Tc(N)-DBODC(5) direct to increase its first-pass extraction keeping unaltered the favorable imaging properties would be desirable. This work describes the synthesis and biological evaluation of a series of novel cationic (99m)Tc-nitrido complexes, of general formula [(99m)TcN(DTC-Ln)(PNP)](+) (DTC-Ln= alicyclic dithiocarbamates; PNP = diphosphinoamine), as potential radiotracers for myocardial perfusion imaging. The synthesis of cationic (99m)Tc-(N)-complexes were accomplished in two steps. Biodistribution studies were performed in rats and compared with the distribution profiles of (99m)Tc(N)-DBODC5 and (99m)Tc-Sestamibi. The metabolisms of the most promising compounds were evaluated by HPLC methods. Biological studies revealed that most of the complexes have a high initial and persistent heart uptake with rapid clearance from nontarget tissues. Among tested compounds, 2 and 12 showed improved heart uptake with respect to the gold standard (99m)Tc-complexes with favorable heart-to-liver and slightly lower heart-to-lung ratios. Chromatographic profiles of (99m)Tc(N)-radioactivity extracted from tissues and fluids were coincident with the native compound evidencing remarkable in vivo stability of these agents. This study shows that the incorporation of alicyclic dithiocarbamate in the [(99m)Tc(N)(PNP)](+) building block yields to a significant increase of the heart uptake at early injection point suggesting that the first-pass extraction fraction of these novel complexes may be increased with respect to the other cationic (99m)Tc-agents keeping almost unaltered the favorable target/nontarget ratios.

Evaluation of 99mTcN-15C5 as a new myocardial perfusion imaging agent in normal dogs and canines with coronary stenosis

This study was designed to evaluate the biodistribution and blood clearance characteristics of 99mTcN-15C5 and its potential as a myocardial perfusion radiotracer. Five normal mongrel dogs were injected with 99mTcN-15C5 intravenously. Blood samples were collected at 0.5, 1, 2, 3, 4, 5, 10, 15, and 30 min postinjection (p.i.). Anterior planar images were acquired at 5, 15, 30, 60, 90, and 120 min p.i. Regions of interest (ROIs) were drawn around heart, liver, and lungs. The raw activity in each ROI was expressed as counts/pixel/min. Heart/liver and heart/lung ratios were calculated by dividing the mean counts in heart ROI by the mean counts in liver and lung ROI, respectively. For comparison, 99mTc-sestamibi was also evaluated in the same five dogs. In dogs with coronary stenoses, single photon emission computed tomography images were acquired at 30, 60, and 120 min after administration of 99mTcN-15C5 with/without adenosine. 99mTcN-15C5 and 99mTc-sestamibi had very similar blood clearance characteristics during the first 30 min p.i. The heart/liver ratio of 99mTcN-15C5 increased from 0.48+/-0.05 at 5 min p.i. to 1.85+/-0.11 at 120 min p.i., whereas the heart/liver ratio of 99mTc-sestamibi was improved only slightly from 0.45+/-0.04 at 5 min p.i. to 0.74+/-0.15 at 120 min p.i. SPECT imaging studies in canines with coronary stenoses indicated that good visualization of the perfusion defect could be achieved at 30 min after administration of 99mTcN-15C5 with the adenosine stress. The combination of high heart uptake and rapid liver clearance makes 99mTcN-15C5 a promising new radiotracer for myocardial perfusion imaging.

Tc-99m-N-MPO: Novel cationic Tc-99m radiotracer for myocardial perfusion imaging

Technetium 99m-N-MPO ([Tc-99m-N(mpo)(PNP5)](+)) is a cationic Tc-99m nitrido complex. The objective of this study is to evaluate its potential as a new radiotracer for myocardial perfusion imaging. Biodistribution studies were performed in Sprague-Dawley rats and guinea pigs to compare the myocardial uptake and excretion kinetics of Tc-99m-N-MPO from noncardiac organs, such as the liver and lungs, with those of the known cationic Tc-99m radiotracers: Tc-99m-N-DBODC5 and Tc-99m-sestamibi. Planar imaging was performed in Sprague-Dawley rats to evaluate the utility of Tc-99m-N-MPO as a myocardial perfusion imaging agent. Metabolism studies were carried out by use of both Sprague-Dawley rats and guinea pigs. In general, the heart uptake of Tc-99m-N-MPO was between that of Tc-99m-sestamibi and Tc-99m-N-DBODC5 over the 2-hour study period. However, the heart-liver ratio of Tc-99m-N-MPO (12.75 +/- 3.34) at 30 minutes after injection was more than twice that of Tc-99m-N-DBODC5 (6.01 +/- 1.45) and approximately 4 times higher than that of Tc-99m-sestamibi (2.90 +/- 0.22). The heart uptake and heart-liver ratio of Tc-99m-N-MPO and Tc-99m-sestamibi in guinea pigs were significantly lower than those obtained in Sprague-Dawley rats. The metabolism studies demonstrated no detectable Tc-99m-N-MPO metabolites in the urine and feces samples of the Sprague-Dawley rats at 120 minutes after injection. In guinea pigs no Tc-99m-N-MPO metabolites were detected in the urine at 120 minutes, but only approximately 60% of Tc-99m-N-MPO remained intact in the feces samples. In contrast, there was no intact Tc-99m-sestamibi detected in urine samples, and less than 15% of Tc-99m-sestamibi remained intact in the feces samples. Planar imaging studies indicated that clinically useful images of the heart may be obtained as early as 15 minutes after injection of Tc-99m-N-MPO. The combination of favorable organ biodistribution and myocardial uptake with rapid liver clearance makes Tc-99m-N-MPO a very promising myocardial perfusion radiotracer worthy of further evaluation in various preclinical animal models.

Evaluation of novel cationic 99mTc(I)–tricarbonyl complexes as potential radiotracers for myocardial perfusion imaging

This report describes the evaluation of three cationic (99m)Tc(I)-tricarbonyl complexes--[(99m)Tc(CO)(3)(L)](+) (L=N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (ME-PNP), N-[15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (15C5-PNP) and N-[18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (18C6-PNP))--as potential radiotracers for myocardial perfusion imaging. Biodistribution, imaging and metabolism studies were performed using Sprague-Dawley rats. It was found that bisphosphine ligands have a significant impact on the biodistribution characteristics and clearance kinetics of their cationic (99m)Tc(I)-tricarbonyl complexes. Among the three radiotracers evaluated in this study, [(99m)Tc(CO)(3)(15C5-PNP)](+) has a very high initial heart uptake and is retained in the rat myocardium for >2 h. It also shows rapid clearance from the liver and lungs. The heart/liver ratio of [(99m)Tc(CO)(3)(15C5-PNP)](+) is approximately 2.5 times better than that of (99m)Tc-sestamibi at 30 min postinjection. [(99m)Tc(CO)(3)(15C5-PNP)](+) is almost identical to (99m)TcN-DBODC5 with respect to heart uptake, heart/lung ratio and heart/liver ratio. Results from metabolism studies show that there is no significant metabolism for [(99m)Tc(CO)(3)(15C5-PNP)](+) in the urine, but it does show a small metabolite peak (<10%) in the radio high-performance liquid chromatography chromatogram of the feces sample at 120 min postinjection. Results planar imaging studies demonstrate that [(99m)Tc(CO)(3)(15C5-PNP)](+) has a much better liver clearance profile than (99m)Tc-sestamibi and might give clinically useful images of the heart as early as 30 min postinjection. [(99m)Tc(CO)(3)(15C5-PNP)](+) is a very promising candidate for more preclinical evaluations in various animal models.

Evaluation of novel cationic 99mTc-nitrido complexes as radiopharmaceuticals for heart imaging: improving liver clearance with crown ether groups

This report describes the evaluation of a series of novel cationic (99m)Tc-nitrido complexes, [(99m)TcN(DTC)(PNP)]+ (DTC = crown ether-containing dithiocarbamates; PNP = bisphosphine), as potential radiotracers for myocardial perfusion imaging. Synthesis of cationic (99m)Tc-nitrido complexes was accomplished in two steps according to literature methods. Biodistribution studies were performed in rats. Planar images of Sprague-Dawley rats administered with 15+/-2 MBq of cationic (99m)Tc radiotracer were obtained using a PhoGama large field-of-view Anger camera. Samples from both urine and feces were analyzed by a reversed-phase radio-HPLC method. Results from biodistribution studies showed that most of the cationic (99m)Tc-nitrido complexes have a high initial heart uptake with a long myocardial retention. They also show a rapid clearance from the liver and lungs. Cationic complexes [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ show heart/liver ratios four to five times better than that of (99m)Tc-sestamibi due to their much faster liver clearance. Their heart uptake and heart/liver ratio are comparable to that of (99m)TcN-DBODC5 within the experimental error. These findings have been confirmed by the results from imaging studies. Radio-HPLC analysis of urine and feces samples indicated that there was very little metabolism of cationic (99m)Tc-nitrido complexes in rats under anesthesia. The key finding of this study is that lipophilicity remains the most important factor affecting both heart uptake and target-to-background (T/B) ratios. Crown ethers are very useful functional groups to improve the liver clearance of cationic (99m)Tc-nitrido complexes. It is the combination of the appropriate DTCs and bisphosphines that results in cationic (99m)Tc-nitrido complexes with high heart uptake and fast clearance from the liver at the same time. The fast liver clearance of [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ suggests that they might be used to obtain clinically useful images as early as 30 min postinjection. [(99m)TcN(L2)(L6)]+ and [(99m)TcN(L4)(L6)]+ are very promising candidates for further evaluation in more extensive preclinical animal models.