Interactions between phospholamban and beta-adrenergic drive may lead to cardiomyopathy and early mortality.

BACKGROUND: Relieving the inhibition of sarcoplasmic reticular function by phospholamban is a major target of beta-adrenergic stimulation. Chronic beta-adrenergic receptor activity has been suggested to be detrimental, on the basis of transgenic overexpression of the receptor or its signaling effectors. However, it is not known whether physiological levels of sympathetic tone, in the absence of preexisting heart failure, are similarly detrimental. METHODS AND RESULTS: Transgenic mice overexpressing phospholamban at 4-fold normal levels were generated, and at 3 months, they exhibited mildly depressed ventricular contractility without heart failure. As expected, transgenic cardiomyocyte mechanics and calcium kinetics were depressed, but isoproterenol reversed the inhibitory effects of phospholamban on these parameters. In vivo cardiac function was substantially depressed by propranolol administration, suggesting enhanced sympathetic tone. Indeed, plasma norepinephrine levels and the phosphorylation status of phospholamban were elevated, reflecting increased adrenergic drive in transgenic hearts. On aging, the chronic enhancement of adrenergic tone was associated with a desensitization of adenylyl cyclase (which intensified the inhibitory effects of phospholamban), the development of overt heart failure, and a premature mortality. CONCLUSIONS: The unique interaction between phospholamban and increased adrenergic drive, elucidated herein, provides the first evidence that compensatory increases in catecholamine stimulation can, even in the absence of preexisting heart failure, be a primary causative factor in the development of cardiomyopathy and early mortality.

Myocardial kinetics of 99m technetium-Q agents: studies in isolated cardiac myocyte, isolated perfused rat heart, and canine regional myocardial ischemia models.

OBJECTIVE: Based on reports of high cellular uptake and low plasma binding of nonreducible mixed ligand Tc(III) cations (Q complexes) and high linear uptake versus blood flow of 99mTc-Q3 in canine hearts, the authors hypothesized that the two Q complexes, 99mTc-Q63 and 99mTc-Q64, would have high cell uptake and better differentiation between ischemic and nonischemic myocardium compared with other 99mTc-based compounds. METHODS: Uptake and retention kinetics of 99mTc-Q63 and 99mTc-Q64 were measured in isolated rat cardiac myocytes, isolated perfused rat hearts, and intact canines and compared with previously reported Q-based compounds, a clinically available 99mTc perfusion agent (sestamibi), and 201Tl. RESULTS: Uptake of Q63, Q64, and sestamibi by isolated cardiac myocytes was similar. Maximum extraction (Emax) of Q64 by isolated perfused rat hearts was greatest among the 99mTc agents (P < 0.02), but net extraction (Enet) of Q64 was not different from Q63 or sestamibi 3 minutes after tracer injection. By 15 minutes, 201Tl Enet was lower than Q63, Q64, and sestamibi (P < 0.05). Among 99mTc agents, the uptake versus flow of Q3, Q63, and Q64 by canine heart was superior to Q12 and sestamibi (P < 0.05). CONCLUSIONS: The activity of Q63 and Q64 in the myocardium is related to actual myocardial blood flow over a broad, clinically relevant range of flows. The ischemic-to-normal zone activity distributions of Q63 and Q64 approximate actual flow in a manner more like that of 201Tl than sestamibi or Q12. These results provide a rational foundation in support of further evaluation of Q63 and Q64 in humans.

Uptake of seven myocardial tracers during increased myocardial blood flow by dobutamine infusion.

RATIONALE AND OBJECTIVES: Direct comparison of myocardial perfusion tracers has been made difficult by variability in experimental models, and by a virtual absence of data comparing tracer uptake to myocardial blood flow under conditions of increased myocardial oxygen consumption, similar to what occurs with dynamic exercise. METHODS: Tracer uptake versus myocardial blood flow was evaluated for thallium-201 (201TI) and six technetium-99m (99mTc) myocardial-imaging agents in 24 open-chest canines with an occluded left-anterior descending coronary artery during dobutamine infusion. Data were fitted to the exponential model y = ax(1 - exp[-PSc/x]), where y is the tissue tracer/g normalized to normal (activity at 1 mL/minute/g) and x is the blood flow measured by the radioactive microsphere method. RESULTS: With dobutamine, myocardial tracer uptake was linear across a wide range of ischemic and hyperemic flows for each tracer. Based on the permeability surface area product, 201TI and 99mTc Q3 provided the best tracer estimate of myocardial blood flow (5.30+/-0.86 mL/minute/g, r = 0.91; 5.46+/-0.58 mL/minute/g, r = 0.94, respectively). Correlation coefficient (r) values for other tracers studied were 99mTc Q4 (r =0.93), 99mTc Q12 (r = 0.93), 99mTc sestamibi (r = 0.90), 99mTc tetrofosmin (r = 0.96), and 99mTc-N-Noet (r = 0.82). CONCLUSIONS: Of the 99mTc tracers examined under conditions of dobutamine-altered myocardial contractility, the myocardial uptake properties of 99mTc Q3 were most similar to those of 201TI.

Technetium-99m Q4: a prototype cationic perfusion radiotracer with myocardial washout.

Technetium-99m Q4 is derived from an existing mixed ligand myocardial tracer (99mTc-Q3) by the addition of an ester group to promote myocardial washout. Six subjects with single-vessel coronary disease documented by angiography and/or Q wave myocardial infarction documented by electrocardiography were studied with 99mTc-Q4 injection during exercise and with comparative thallium-201 tomography. Six healthy volunteers were also studied with 99mTc-Q4 imaging following injection at peak exercise. Tomographic images with 99mTc-Q4 and 201Tl each provided correct assessment of the presence or absence of coronary disease in 22 of 30 myocardial segments (73.3%). Six myocardial segments showed defect reversibility with 99mTc-Q4, whereas 14 segments showed reversibility with 201Tl, but the latter included three segments with no angiographic or electrocardiographic evidence of disease. In both normals and subjects with coronary artery disease, significant global washout of 99mTc-Q4 was observed over 4 h. For five patients with angiographic evidence of unrevascularized coronary artery stenosis, the ischemic to normal zone count ratio increased from 0. 782+/-0.107 at 45 min postexercise to 0.891+/-0.115 at 4 h postexercise (P = 0.016), suggesting occurrence of differential washout. It is concluded that addition of an ester group functionality to a previously studied mixed ligand cardiac tracer promotes global and regional myocardial tracer washout. Nevertheless, demonstration of perfusion defect reversibility with comparable frequency to that observed with 201Tl stress and reinjection images, required separate injections of 99mTc-Q4 at peak stress and at rest.

Rhenium-188(Sn)HEDP for treatment of osseous metastases.

UNLABELLED: Rhenium-188 (tin) hydroxyethylidine diphosphonate [188Re(Sn)HEDP] is a new radiopharmaceutical that localizes in skeletal metastases and emits beta particles that may be therapeutically beneficial. METHODS: It was evaluated by in vitro and in vivo testing in the laboratory, in animals and in humans using 188Re from a variety of sources. It may be produced by a desk-top method developed previously for 186Re(Sn)HEDP using 188Re produced through neutron irradiation of either enriched 187Re or naturally occurring rhenium targets or the use of a 188W/188Re generator. RESULTS: So long as the mass of rhenium in the 188Re-perrhenate to be processed into 188Re(Sn)HEDP is at least 100 microg, satisfactory radiochemical yields and purity may be obtained by all methods. The 188Re(Sn)HEDP has biodistribution and radiation dosimetry characteristics that are similar to those noted previously for 186Re(Sn)HEDP and appears to result in similar benefits and toxicities in patients with skeletal metastases. External radiation exposure monitoring indicates that, only 4 hr after a therapeutic administration of 1110 MBq (30 mCi) of 188Re(Sn)HEDP, average exposure rates at 1 meter from the patient would be only 0.5 mR/hr. CONCLUSION: Same-day, on-demand, outpatient therapy of disseminated skeletal metastases appears to be feasible with 188Re(Sn)HEDP.

Extraction and retention of technetium-99m Q12, technetium-99m sestamibi, and thallium-201 in isolated rat heart during coronary acidemia.

Technetium-99m Q12 and 99mTc-sestamibi are cationic lipophilic myocardial perfusion imaging tracers. Because myocardium in areas of ischemia becomes acidotic, experiments were designed to differentiate the effects of myocardial perfusate pH on radiotracer extraction and retention independent of substrate availability. We hypothesized that 99mTc-Q12 and 99mTc-sestamibi single-pass uptake and retention would be unaffected by a modest reduction in coronary perfusate pH. Isolated rat hearts were perfused at constant flow with Krebs-Henseleit buffer enriched with bovine red blood cells (20%). The indicator dilution method was used to measure the maximum extraction (Emax) and net extraction (Enet) of thallium-201 and 99mTc-Q12 (n = 8) or 201Tl and 99mTc sestamibi (n = 7) during baseline perfusion (pH = 7.4), during acidemic (pH = 6.7) perfusion, and during a restitution period with normal perfusate (pH = 7.4). 201Tl Emax (0.71+/-0.03) was greater than either 99mTc-Q12 or 99mTc-sestamibi Emax (0.27+/-0.02 and 0.26+/-0.01 respectively, P<0.0001). Acidemia significantly reduced 201Tl Emax (0.65+/-0.03, P<0.02) but not 99mTc-Q12 or 99mTc-sestamibi Emax (0.25+/-0.02 and 0.24+/-0.02 respectively). During control perfusion Enet of 201Tl was greater than that of 99mTc-Q12 at 3 and 5 min and greater than that of 99mTc-sestamibi at 3 min. 99mTc-Q12 Enet was less than 99mTc-sestamibi Enet at 3, 5, and 10 min. Acidemia decreased 201Tl and 99mTc-sestamibi Enet at 3, 5, and 10 min but had no effect on 99mTc-Q12 Enet. It is concluded that Emax of 99mTc-Q12 is less than that of 201Tl but is not different from that of 99mTc-sestamibi. Enet of 99mTc-Q12 is less than that of 99mTc-sestamibi.

Flow versus uptake comparisons of thallium-201 with technetium-99m perfusion tracers in a canine model of myocardial ischemia.

UNLABELLED: We investigated the myocardial flow kinetics of six putative radioperfusion agents (99mTc-Q3, 99mTc-Q4, 99mTc-Q12, 99mTc-sestamibi, 99mTc-tetrofosmin and 99mTcN-NOET) and 201Tl in a canine model of myocardial ischemia with pharmacologic coronary artery vasodilation. METHODS: In 31 open-chest dogs with acute coronary occlusion, dipyridamole (approximately 0.56 mg/kg) was infused intravenously, followed by a perfusion tracer injection and radioactive microspheres for myocardial blood flow (MBF) measurement. The paired data were normalized using three techniques; average, normal or maximum myocardial tracer activity and MBF. RESULTS: The upper limit of MBF obtained for the group of tracers ranged from 4.2 ml/min/g to 8.2 ml/min/g. There was a statistically significant (p < 0.0001) linear correlation (r = 0.87-0.98) between the normalized myocardial activity and the normalized MBF values of each of the tracers. The slope of the curve normalized by average for 201Tl (0.83) was greater than those for the 99mTc tracers, and the intercept (0.07) was lower than those for the 99mTc tracers. Slopes and intercepts for the 99mTc agents were as follows: 99mTc-Q3, 0.81 and 0.18; 99mTc-Q4, 0.61 and 0.41; 99mTc-Q12, 0.63 and 0.39; 99mTc-sestamibi, 0.62 and 0.34; 99mTc-tetrofosmin, 0.68 and 0.32; and 99mTcN-NOET, 0.71 and 0.29, respectively. CONCLUSION: In an anesthetized open-chest canine model of regional myocardial ischemia with dipyridamole induced hyperemia, 201Tl shows a more ideal relationship between tracer uptake and MBF than do the 99mTc-based agents. Of the various 99mTc-based imaging agents studied, the myocardial flow kinetics of 99mTc-Q3 appear to be closest to ideal. This relationship is maintained regardless of the normalization technique used. This may, in theory, imply a higher sensitivity in discerning ischemic from normal myocardium and a role in diagnostic nuclear imaging for 99mTc-Q3.

99mTc-2GAM: a tracer for renal imaging.

We propose a renal imaging agent, the 99mTc complex of the bidentate-N,S chelate N-(mercaptoacetyl)glycine (99mTc-2GAM), with the imaging characteristics of 99mTc-DMSA but a faster kidney uptake; chemical evidence supports the formulation of 99mTc-2GAM as [Tc(v)(O)(GAM)2]-. After biodistribution and toxicity studies in animals, 99mTc-2GAM was evaluated in five normal volunteers. 99mTc-2GAM is rapidly cleared from the blood (t1/2 = 9 min) and 50% of the ID is excreted in the urine in the first 2 h. Dynamic data show a rapid renal uptake that increases up to 1 h with no significant wash-out between 1 and 8 h. The uptake in each kidney ranges from 11.3% to 20.7% ID. Low, stable liver uptake is observed. No significant activity is detected in other organs. We showed no differences between 99mTc-2GAM and 99mTc-DMSA compared in three patients with unilateral kidney disease. We conclude that 99mTc-2GAM has good practical and dosimetric features for renal imaging.

Effects of ouabain on technetium-99m-Q12 and thallium-201 extraction and retention by isolated rat heart.

UNLABELLED: The mechanisms of myocardial extraction and retention of the new cationic lipophilic radionuclide imaging agent 99mTc-Q12 are currently unknown. We hypothesized that 99mTc-Q12 has satisfactory single-pass extraction independent of active transport processes and longer cellular retention than 201Tl for rapid and sustained cardiac imaging to differentiate perfusion defects. METHODS: Isolated rat hearts were perfused at constant flow with Krebs-Henseleit buffer enriched with bovine red blood cells (30%-40%). The indicator dilution method was used to measure the single-pass maximum extraction (Emax) and net extraction (Enet(t)) of 201Tl and 99mTc-Q12 over 15 min during control perfusion (n = 11) and during normal (1 microM, n = 6) and high cardiotoxic (50 microM, n = 11) dose infusions of the digitalis glycoside, ouabain. RESULTS: The Emax of 201Tl was greater than 99mTc-Q12 Emax (0.73 +/- 0.01 and 0.29 +/- 0.01, respectively). At 3 min of perfusion, 201Tl Enet was greater than 99mTc-Q12 Enet (0.40 +/- 0.01 and 0.11 +/- 0.00, respectively). Between 3 and 15 min, 201Tl Enet was decreasing by a rate of 2% per minute while 99mTc-Q1 2 Enet was decreasing by less than 0.1 % per minute. Ouabain decreased 201TI Emax but did not change 99mTc-Q12 Emax. High-dose ouabain decreased 201Tl Enet at 3 min and 99-Tc-Q12 Enet at 10 and 15 min. CONCLUSION: Ouabain reduced 201Tl Emax but not 99mTc-Q12 Emax. Therefore, the cellular extraction process for 99mTc-Q12 is different from that of 201Tl. Since the Enet(t) of 99mTc-Q12 was reduced in the presence of high doses of ouabain while Emax was unchanged, 99mTc-Q12 extraction and retention appear to be controlled by different processes. Extraction and release kinetics of 99mTc-Q12 were not changed with a low dose analogous to the human therapeutic levels of ouabain.

Reliable preparation of 99mTc (V) DMSA by a simple modified method using a commercial kit for 99mTc (III) DMSA.

99mTc pentavalent dimercaptosuccinic acid [99mTc (V) DMSA], a useful agent for imaging thyroid medullary carcinoma and other tumors, can be reliably prepared by addition of NaHCO3 and then Na99mTcO4 to a commercial kit for 99mTc trivalent DMSA [99mTc (III) DMSA], followed by bubbling oxygen through the solution for 10 min. 99mTc (V) DMSA made by this method is radiochemically pure and stable for 24 h, and it gives a rat biodistribution similar to that of the agent made by previous methods. Clinical biodistribution and radiation dosimetry studies are planned.

Comparison of imaging properties of technetium 99m Q12 and technetium 99m Q3 in humans.

BACKGROUND: This study was a direct comparison of the imaging characteristics of 99mTc-labeled Q12 (99mTc-Q12) and 99mTc-labeled Q3 (99mTc-Q3) in the same patients. METHODS AND RESULTS: In 10 patients with known angiographic coronary artery anatomy, 99mTc-Q12 and 99mTc-Q3 myocardial imaging were performed. Tomographic myocardial imaging was started 15 minutes after tracer injection at rest and with treadmill exercise. Ratios of heart-to-lung and heart-to-liver activity were calculated from the anterior plane projections of the tomograms at 20 minutes after tracer injection. The presence or absence of angiographic coronary artery disease was correctly determined from 99mTc-Q12 images in 10 of 10 patients with 99mTc-Q12 and in 9 of 10 patients with 99mTc-Q3. The presence or absence of a greater than 50% stenosis in an individual coronary vessel was correctly predicted for 26 of 30 vessels with 99mTc-Q12 (87%) and in 27 of 30 vessels with 99mTc-Q3 (90%, p = NS vs 99mTc-Q12). Mean heart-to-lung activity ratio at rest was 1.50 for 99mTc-Q12 and 1.93 for 99mTc-Q3 (p < 0.01). Mean heart-to-liver activity ratio at rest for 99mTc-Q12 was 0.78 versus 0.54 for 99mTc-Q3 (p < 0.0001). CONCLUSIONS: In 10 patients with chest pain and angiographically defined coronary anatomy, 99mTc-Q12 and 99mTc-Q3 provided similar detection of coronary artery stenoses. At 20 minutes after tracer injection, heart-to-liver activity ratios were more favorable for 99mTc-Q12 than for 99mTc-Q3, but 99mTc-Q3 resulted in a more favorable ratio of heart-to-lung activity.

Comparison of technetium 99m Q12 and thallium 201 for detection of angiographically documented coronary artery disease in humans.

BACKGROUND: 99mTc-labeled Q12 (99mTc-Q12) is a new imaging agent that produces myocardial visualization in humans. This study examined the hypothesis that a 100-minute rest-exercise tomographic imaging protocol after injection of 99mTc-Q12 can be used to detect the presence or absence of coronary artery stenoses. METHODS AND RESULTS: Imaging with 201Tl and 99mTc-Q12 was performed in 20 patients with angiographically documented coronary artery disease and 10 "normal" subjects including two patients with chest pain and normal coronary arteriograms and eight subjects with a very low likelihood of occlusive coronary disease. 99mTc-Q12 was imaged beginning 15 minutes after injection at rest and with exercise. In the 20 patients, a corresponding myocardial defect was detected in blinded fashion in 18 with 201Tl and 17 with 99mTc-Q12 (difference not significant). Of 10 patients without evidence of coronary disease, nine had a normal 201Tl scan and eight had a normal 99mTc-Q12 scan (difference not significant). Agreement of 99mTc-Q12 and 201Tl imaging for detection of regional myocardial perfusion defects was excellent (kappa = 0.88). Identification of the presence or absence of angiographically documented coronary disease in individual coronary artery distributions was 80% and 82% for 201Tl imaging and 73% and 87% for 99mTc-Q12 (difference not significant). CONCLUSION: 99mTc-Q12, used in a rest-exercise sequence that can be completed in 100 minutes, provided identification of regional myocardial perfusion defects similar to that of 201Tl.

Myocardial uptake and kinetic properties of technetium-99m-Q3 in dogs.

UNLABELLED: We postulated that 99mTc-Q3, a cationic imaging agent, produces myocardial activity related to myocardial blood flow during myocardial ischemia and pharmacologic coronary artery vasodilation, and shows little or no myocardial redistribution over 4 hr after intravenous injection. METHODS: In six Group 1 dogs, the chest was opened, the left circumflex coronary artery was acutely ligated, and dipyridamole (0.32, 0.56 or 0.84 mg/kg) was infused into the right atrium, followed by 10 mCi of 99mTc-Q3. Myocardial blood flow was measured by radiolabeled microspheres. The animals were euthanized and 357 myocardial samples were assayed in a well counter for 99mTc activity. One week later, radiolabeled microsphere activity was counted and myocardial blood flow calculated. In nine Group 2 dogs, a variable occluder was placed around the left circumflex coronary artery and an ischemic level of circumflex blood flow was maintained constant over 4 hr as measured by an ultrasonic flow meter. Dipyridamole (0.56 mg/kg) was then infused into the right atrium followed by 10 mCi of 99mTc-Q3. Gamma camera images were acquired at 5, 15, 30, 60, 120 and 240 min following 99mTc-Q3 injection. Microsphere blood flow and endocardial biopsies (n = 6 dogs) were performed at 30, 60, 120 and 240 min following 99mTc-Q3 injection. RESULTS: In the Group 1 animals, 99mTc activity (y) was related to myocardial blood flow (x) from 0 to 6.1 ml/min/g by the relationship y = 0.83X + 0.18, r = 0.95, p = 0.0001. The scintigraphic ratio of myocardial perfusion defect zone counts-to-normal myocardial zone counts (0.54 +/- 0.05 at 30 min) remained constant over 4 hr, as did technetium counts from direct endocardial sampling. Scintigraphic count ratios allowed discrimination between perfusion defect and normal myocardial regions beginning at 5 min following 99mTc-Q3 injection. CONCLUSIONS: Over a range of myocardial blood flows from 0 to 6.1 ml/min/g, 99mTc-Q3 myocardial activity is related to myocardial flow at the time of tracer injection. Technetium-99m-Q3 shows no evidence of myocardial redistribution over a 4-hr period.

Comparison of technetium-99m-Q3 and thallium-201 for detection of coronary artery disease in humans.

UNLABELLED: Technetium-99m-Q3 is a myocardial imaging agent that produces prompt myocardial visualization in humans. METHODS: In 19 patients with angiographic coronary artery disease, 2 patients with no angiographic coronary artery stenosis greater than 50% of the luminal diameter and 6 healthy volunteers, exercise and resting myocardial imaging were performed with 99mTc-Q3 and also with 201Tl. Technetium-99m-Q3 imaging began 15 min after injection at rest and with exercise, in a complete imaging sequence that required less than 100 min. RESULTS: Overall accuracy for coronary disease detection was 78% (21 true-positive or true-negative studies among 27 study participants) by tomographic thallium imaging versus 89% for 99mTc-Q3 tomographic imaging (p = ns). Accuracy for detection of individual coronary stenoses was 75% (61 true-positive or true-negative coronary segment classifications among 81 total coronary segments) for 201Tl imaging and 83% for 99mTc-Q3 imaging (p = ns). CONCLUSIONS: Technetium-99m-Q3 when used in a rest-exercise sequence that can be completed in 100 min appears to provide comparable diagnostic accuracy to 201Tl for overall coronary disease detection and detection of individual coronary artery stenoses.

Kinetic properties of 99mTc-Q12 in canine myocardium.

BACKGROUND: 99mTc-Q12 is a new Tc(III) perfusion imaging agent that permits prompt myocardial visualization in humans. We postulated that 99mTc-Q12 myocardial activity is related to actual myocardial blood flow during conditions of myocardial ischemia and pharmacological coronary artery vasodilation and that 99mTc-Q12 shows little or no myocardial redistribution as long as 4 hours after intravenous injection. METHODS AND RESULTS: In seven anesthetized, open chest dogs, the left circumflex coronary artery was occluded, and dipyridamole (0.32 or 0.56 mg/kg) was infused into the right atrium, followed by 10 mCi of 99mTc-Q12. Myocardial blood flow was measured by radiolabeled microspheres. The animals were euthanized, and a total of 315 myocardial samples were assayed in a well counter for 99mTc activity. One week later, radiolabeled microsphere activity was determined, and myocardial blood flow was calculated. 99mTc activity (y) was related to myocardial blood flow (x) from 0 to 2 mL.g-1 x min-1 by the relation y = 0.64x + 0.35 (r = .88, P = .0001). In 14 additional anesthetized, open chest dogs, an occluder was placed around the left circumflex coronary artery, and an ischemic level of circumflex blood flow was maintained constant over 4 hours as measured by an ultrasonic flowmeter. Dipyridamole (0.56 mg/kg) was infused intravenously beginning 15 minutes after coronary occlusion and then followed by 10 mCi of 99mTc-Q12. Gamma camera images, hemodynamics, microsphere blood flow, and endocardial biopsies (latter in six dogs) were performed at 30, 60, 120, and 240 minutes after 99mTc-Q12 injection. Myocardial blood flow in the distribution of the left anterior descending artery decreased by 29.6% from 30 to 240 minutes (P < .05), whereas left circumflex blood flow increased by 40.4% from 30 to 120 minutes (P < .05) as the dipyridamole hemodynamic effects dissipated. Nevertheless, the ratio of myocardial perfusion defect zone counts to normal myocardial zone counts remained constant over 4 hours, as did the technetium counts from the needle biopsy endocardial samples. CONCLUSIONS: Over a limited range of myocardial blood flows from 0 to approximately 2 mL.g-1 x min-1, 99mTc-Q12 myocardial activity is related to actual myocardial flow at the time of tracer injection. 99mTc-Q12 shows no evidence of myocardial redistribution.

A new, general synthetic route to multidentate N,S ligands for use in technetium-99m radiopharmaceuticals. Preparation of diamido disulfur, diamino dithiol, and tripodal N3S3 prototypes. Comparative biodistributions of [99mTcvO-DADS]- analogues which contain 5,5,5- and 5,7,5-membered chelate ring systems.

A new, versatile synthetic route to a variety of tetradentate N2S2 and hexadentate N3S3 ligands for use in technetium-99m radiopharmaceuticals has been developed. The key reaction employs 1-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline (EEDQ) for coupling an appropriate di- or triamine with S-protected thioglycolic acid. Selected DADS (diamido disulfur) and DADT (diamino dithiol) and analogues derived from ethanediamine-1,2 and butanediamine-1,4, as well as a tripodal N3S3 analogue, were synthesized in high yield. The labeling of DADS analogue ligands derived from butanediamine-1,4 (DADS-bn) with 99mTc results in a single radiochemical product, or the expected number of stereoisomeric products. FAB MS analysis, using 99Tc, indicates that DADS-bn ligands form a tetradentate 5,7,5-membered ring chelate system with the monooxo Tc(V) core: [TcO-DAD-bn]-. In rat biodistribution studies the DADS-en and DADS-bn complexes show very similar biological activity. Phenyl substituents on the 7-membered ring give rise to a 99mTc complex of increased lipophilicity, increased liver uptake, and minimal hepatobillary clearance. Thus, new classes of DADS ligand analogues which contain a 5,7,5-membered chelate ring system are readily synthesized and labeled with 99mTc to form stable complexes. The presence of the 7-membered chelate ring allows for facile introduction of pendant groups into the ligand system, and thus for a ready route to control the biodistribution of the resulting 99mTc radiopharmaceutical. The 99mTc labeling of the DADT analogues derived from butanediamine-1,4 provided to be erratic, despite the use of a variety of labeling techniques; the larger ring system of DADT-bn apparently does not favor the monooxo Tc(V) core and appears to generate a mixture of mono- and dioxo Tc(V) cores.