Iodomethylated fatty acid metabolism in mice and dogs

The myocardial uptake of fatty acids labeled with radioactive iodine and injected i.v. can only be evaluated with SPECT if their oxidation kinetics is slow enough. For this reason, we evaluated different iodomethylated fatty acids in mice and dogs to determine which of them shows the highest myocardial uptake and the slowest oxidation. The most suitable was found to be 16-iodo-3-methyl hexadecanoic acid (mono beta) since its myocardial fixation was the same as that of the reference, i.e. 16-iodo-9-hexadecenoic acid (IHA), whereas it was degraded more slowly. Thirty min after injection of mono beta into dogs, the decrease in myocardial activity with respect to the maximum was two fold less than after IHA injection. The myocardial uptake of the two dimethylated fatty acids studied, i.e. 16-iodo-2,2-methyl hexadecanoic acid and 16-iodo-3,3-methyl hexadecanoic acid, was less than that of IHA in mice and dogs. In the latter, the myocardial uptake was so small that we were unable to study the time course of its activity. Consequently, these dimethylated fatty acids are not suitable for the study of the myocardial uptake of fatty acids in man.     

Myocardial metabolism of radioiodinated methyl-branched fatty acids

Methylated fatty acids labeled with radioactive iodine have been proposed as a means of studying regional myocardial uptake of fatty acids in man. To investigate the methylated fatty acid that is best adapted for an assessment of uptake, we have studied the influence of the number and the position of the methyl groups of IFA intracellular metabolism; 16-iodo-2-methyl-hexadecanoic (mono-alpha), 16-iodo-2,2-methyl hexadecanoic (di-alpha), 16-iodo-3-methyl-hexadecanoic (mono-beta), and 16-iodo-3,3-methyl-hexadecanoic (di-beta) acids were injected into the coronary arteries of isolated rat hearts. Intracellular analysis shows that the degradation of mono-alpha was always lower than that of IHA and the storage was always much higher. The differences between mono-beta and IHA were similar to those observed with mono-alpha, but were much more pronounced. With the two dimethylated IFAs there was an inhibition of both oxidation and esterification which led to an accumulation of free FAs in myocardial cells. In conclusion, mono-beta, di-alpha, and di-beta are potentially suitable for studying the cellular uptake of IFA since all of them, and particularly the dimethylated IFAs, have a low oxidation rate.     

Metabolism of methyl-branched iodo palmitic acids in cultured hepatocytes

The metabolic fate of methyl-branched iodo fatty acids was studied in primary culture of rat hepatocytes. We compared 16-iodo-2-R,S-methyl palmitic acid (2-Me), which can be oxidized, with 16-iodo-3-R,S-methyl palmitic acid (3-Me) which can be oxidized only after an initial oxydation and with 16-iodo-2,2-dimethyl palmitic acid (2,2-Me₂) and 16-iodo-3,3-dimethyl palmitic acid (3,3-Me₂) which cannot be oxidized at all. The normal fate of natural fatty acids was given by comparative experiments with [1-¹⁴C] palmitic acid. Monomethyl-branched iodo fatty acids were taken up in the same range as palmitic acid but more than dimethyl-branched iodo fatty acids. After a 15-h incubation, acido-soluble products (ASP) accounted for 75% of the radioactivity taken up as 16-iodo-2-methyl palmitic acid, 50% as other methyl-branched iodo fatty acids and only 30% as palmitic acid, which indicated that all the methyl-branched iodo fatty acids underwent a strong deiodination process. Fatty acids were esterified in the following order: palmitic acid >16-iodo-3-R,S-methyl palmitic acid>16-iodo-2-R,S-methyl palmitic acid>16-iodo-2,2-dimethyl palmitic acid>16-iodo-3,3-dimethyl palmitic acid. Cultured hepatocytes, labelled for 3 h with the various fatty acids and reincubated for 12 h without fatty acid, secreted large amounts of free dimethylbranched iodo fatty acids as compared to the monomethyl ones and palmitic acid. Only hepatocytes prelabelled with 16-[¹²⁵I]iodo-2,2-dimethyl palmitic acid exhibited an appreciable secretion of labeled triglycerides, but at a lower rate than with [1-¹⁴C] palmitic acid. Conversely, the 16-iodo-monomethyl palmitic acids remained chiefly in hepatocyte triglycerides. Minute amounts of 16-iodo-methyl-branched-palmitic acids were found in hepatocyte or secred phospholipids as compared with palmitic acid. This metabolic fate of methyl-branched iodo palmitic acids argues against their utilization as imaging probes to monitor in vivo the synthesis and the secretion of triglycerides by the liver.     

Effect of glucose on the distribution of iodine-123-IHA-16 between esterification and oxidation in canine myocardium

To evaluate the effect of glucose perfusion on the myocardial metabolism of [123I]-16-iodo-9-hexadecenoic acid (IHA), the latter was injected intravenously into six fasting dogs perfused with a solution lacking glucose (controls) and seven fasting dogs perfused with glucose and insulin. The distribution of myocardial 123I among iodides, free IHA, and esterified IHA was measured in myocardial biopsy specimens. The increase in esterification and decrease in oxidation of IHA due to glucose were quantified using a compartmental mathematical model of myocardial IHA metabolism. Subsequently, in six control and six glucose-perfused dogs, cardiac radioactivity was measured with a scintillation camera for 1 hr following i.v. injection of IHA. Four different methods were used to analyze the myocardial time-activity curves and to calculate the distribution of IHA between oxidation and esterification. Results comparable to those provided by analysis of biopsy specimens can be obtained by considering the curve to be the sum of an exponential and a constant, or by analyzing it with a compartmental mathematical model.     

Kinetics of iodomethylated hexadecanoic acid metabolism in the rat myocardium: influence of the number and the position of methyl radicals

The methyl-branched fatty acids, if radioiodine labelled in alpha position, are potentially adapted to a selective study of FA myocardial uptake. To determine the position and the number of methyl radicals that are necessary to obtain a maximal uptake and a minimal degradation, we measured time-activity evolution of isolated and perfused rat hearts after an injection of iodinated fatty acids which are mono- or dimethylated in alpha or beta position. Except for dimethyl fatty acid, the uptake is similar for all fatty acids studied to that of the straight chain analogue; beta mono- or dimethyl fatty acids seem best adapted to a study of the uptake because alpha monomethyl fatty acids undergo a metabolic degradation and alpha mono- and dimethyl fatty acids induce ventricular fibrillations.     

Metabolism of methyl-branched iodo palmitic acids in cultured hepatocytes

The metabolic fate of methyl-branched iodo fatty acids was studied in primary culture of rat hepatocytes. We compared 16-iodo-2-R,S-methyl palmitic acid (2-Me), which can be beta oxidized, with 16-iodo-3-R,S-methyl palmitic acid (3-Me) which can be beta oxidized only after an initial alpha oxydation and with 16-iodo-2,2-dimethyl palmitic acid (2,2-Me2) and 16-iodo-3,3-dimethyl palmitic acid (3,3-Me2) which cannot be beta oxidized at all. The normal fate of natural fatty acids was given by comparative experiments with [1-14C] palmitic acid. Monomethyl-branched iodo fatty acids were taken up in the same range as palmitic acid but more than dimethyl-branched iodo fatty acids. After a 15-h incubation, acido-soluble products (ASP) accounted for 75% of the radioactivity taken up as 16-iodo-2-methyl palmitic acid, 50% as other methyl-branched iodo fatty acids and only 30% as palmitic acid, which indicated that all the methyl-branched iodo fatty acids underwent a strong deiodination process. Fatty acids were esterified in the following order: palmitic acid greater than 16-iodo-3-R,S-methyl palmitic acid greater than 16-iodo-2-R,S-methyl palmitic acid greater than 16-iodo-2,2-dimethyl palmitic acid greater than 16-iodo-3,3-dimethyl palmitic acid. Cultured hepatocytes, labelled for 3 h with the various fatty acids and reincubated for 12 h without fatty acid, secreted large amounts of free dimethyl-branched iodo fatty acids as compared to the monomethyl ones and palmitic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fatty acid myocardial imaging using 123I-β-methyl-iodophenyl pentadecanoic acid (BMIPP): comparison of myocardial perfusion and fatty acid utilization in canine myocardial infarction (Occlusion and reperfusion model)

To evaluate the relationship between myocardial perfusion and fatty acid metabolism in canine myocardial infarction, 16 dogs were studied using thallium and ¹²³I--methyl-iodophenyl pentadecanoic acid (BMIPP). Eight dogs (group A) had left anterior coronary arterial occlusion (6 h ligation), 6 dogs (group B) had reperfusion (3 h ligation and 1 h reperfusion) and 2 dogs served as the normal control. Myocardial imaging with BMIPP was excellent, owing to its higher uptake and longer retention in myocardium and rapid blood disappearance in addition to diminished liver and lung uptake. The mean half time value which was generated from the BMIPP myocardial washout curve, was significantly larger in the reperfused myocardium. The gamma camera imaging showed uncoupling of BMIPP and thallium (BMIPP uptake greater than thallium uptake) in five dogs in group B. On the other hand, all dogs in group A had a persistent defect in BMIPP and thallium uptake. Our findings indicate that the combination of BMIPP and thallium for myocardial imaging supply different information about the zone of infarction and ischemia, which may be useful for the assessment of myocardial viability.     

ω-Halofatty acids: A probe for mitochondrial membrane integrity

Long-chain -halofatty acids, especially -¹²³I-iodoheptadecanoic acid (IHA), are widely used clinically as radiopharmaceuticals for functional heart imaging. The metabolic interpretation of the various elimination rates, however, remains in dispute. It has been previously shown (Kloster and Stöcklin 1982) that in isolated perfused guinea-pig hearts halide diffusion from the mitochondrion to the blood is the rate-determining step of IHA pharmacokinetics in normal myocardium. We have now extended these in vitro experiments to normal and globally ischaemic isolated perfused rabbit hearts. Again, in normal hearts a single phase iodide elimination half-time (14.3±2.1 min) was observed. In hearts made globally ischaemic for 90 min, the iodide elimination was biphasic with a first fast phase (T_1/2=3.8±0.49 min) and a late slow phase (T _1/2=60.5±14.0 min). The first fast phase is attributed to iodide ion released by residual -oxidation (more rapid than in normal hearts due to damaged membranes in ischaemia), while the late slow phase is explained by -oxidation of IHA slowly released by hydrolysis of intracellular lipid stores. These data were compared with published data from investigations in patients which seem to support our interpretation.     

Comparison of iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane for imaging of the dopamine transporter in the living human brain

Several cocaine congeners are of potential for imaging the dopamine transporter (DAT). Previous studies have shown that iodine-123 labelled 2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) is a promising radiotracer for imaging the serotonin (5-HT) and dopamine (DA) transporters in the living human brain with single-photon emission tomography (SPET). [¹²³I]-CIT was found to be not very practical for 1-day DAT imaging protocols since peak DAT uptake occurs later than 8 h. Here we report a pilot comparison of [¹²³I]-CIT and 2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([¹²³I]-CIT FP), using SPET imaging in four healthy male subjects. Peak uptake of [¹²³I]-CIT-FP into the basal ganglia occurred earlier (3–4 h after injection of tracer) than that of [¹²³I]-CIT (>8 h). However, the specific DAT binding of [¹²³I]-CIT-FP in the basal ganglia was somewhat less (0.813±0.047) than that of [¹²³I]-CIT (0.922±0.004). Imaging quality is excellent with both tracers and they are potentially of value for brain imaging in various neuropsychiatric disorders.     

Sequential sampling: A new acquisition technique for fatty acid kinetics from quasi-simultaneous multiple projections

Studies of myocardial metabolism by rapidly catabolized fatty acids like -I-123-heptadecanoic acid (IHA) are usually limited to one planar view of require sophisticated equipment, such as bidirectional slant-hole collimators or seven-pinhole collimators for multiplane or tomographic views. To solve this problem a normal SPECT camera was utilized to acquire sequentially sampled dynamic studies from up to six different views. This was done by a periodically repeated sequence of acquisitions in different projections, which followed one another clockwise. This procedure overcomes the single-plane limitations of the usual IHA dynamic studies. It reveals regional myocardial patterns of tracer uptake and elimination not obtainable from any single viewing angle. In this way one methodological disadvantage relative to thallium perfusion studies is removed. Furthermore, the non-invasive diagnosis of cardiomyopathies, for which no other radioisotope procedure is appropriate, should be improved using this new method.     

Effect of 3-methyl-branching on the metabolism in rat hearts of radioiodinated iodovinyl long chain fatty acids

The metabolism of two new 3-methyl-branched iodovinyl fatty acids in rat hearts was evaluated by determining the subcellular and lipid pool distribution of these radiolabeled analogues after intravenous injection. Methyl branching had been introduced into the straight chain analogue, 19-iodo-18-nonadecenoic acid (IVN), to produce the monomethyl analogue, 19-iodo-3-(R,S)-methyl-18-nonadecenoic acid (BMIVN) and the dimethyl derivative, 19-iodo-3,3-dimethyl-18-nonadecenoic acid (DMIVN) in the hope of inhibiting oxidation. Since the presence of 3-methyl branching results in delayed myocardial clearance in rats, differences were sought in the lipid and subcellular distribution of these branched analogues that might correlate with the prolonged retention and reflect differences in metabolism. Hearts of rats injected intravenously with the radiolabeled fatty acids were removed and homogenized and the homogenates partitioned between the chloroform-methanol (organic) fraction and the aqueous fraction. Comparison of the distribution of radioactivity between the organic and aqueous fractions showed that most of the DMIVN and BMIVN activity was in the organic fraction with IVN activity initially divided equally between the two fractions. Identification of the lipid components of these organic fractions showed that there was slow incorporation of DMIVN into the triglyceride and polar lipid fractions with a slow loss from the free fatty acid fraction. With the straight chain IVN analogue which shows rapid washout from rat hearts, there was loss of activity from all 3 lipid components during the 60 min. The monomethyl branched BMIVN analogue demonstrated predominant storage in the polar lipid fraction with some incorporation into triglycerides. Subcellular distribution studies of the three analogues also showed differences that correlated with the observed differences in heart retention properties. With the unbranched IVN analogue, radioactivity was found primarily in the cytoplasmic fraction 30 min after injection, whereas the branched analogues demonstrated a much higher association with the microsomal and mitochondrial fractions of the heart. In rats fed prior to injection, these differences in the subcellular distribution profiles were minimized. The lipid and subcellular distribution patterns reported here for the methyl branched analogues as compared to those of the straight chain iodovinyl fatty acid may provide some understanding as to the mechanisms of retention in rat myocardium.Research supported by the Office of Health and Environmental Research, U.S. Department of Energy, under contract DE-AC0 5-840 R21400 with Martin Marietta Energy Systems, Inc.     

Significance of myocardial uptake of iodine 123-labeled beta-methyl iodophenyl pentadecanoic acid: Comparison with kinetics of carbon 11-labeled palmitate in positron emission tomography

Background

A radioactively labeled beta-methyl branched fatty acid analog,¹²³I-15-(p-iodophenyl)-3-methyl pentadecanoic acid (BMIPP), has been developed to probe regional myocardial fatty acid metabolism. However, the significance of BMIPP uptake in the myocardium remains unclear.

Methods and Results

To evaluate the significance of BMIPP uptake, single-photon emission computed tomography was performed 30 minutes after injection of BMIPP, and²⁰¹Tl-labeled single-photon emission computed tomography was taken on a separate day in 10 patients. Findings of BMIPP and²⁰¹Tl-labeled imaging were compared with the data obtained from positron emission tomography with¹¹C-labeled palmitate. The BMIPP uptake (percent of maximum) was significantly correlated with the early uptake (percent) and delayed uptake (percent) of¹¹C-labeled palmitate (r=0.659 andr=0.687, respectively) (p<0.01 each), whereas it was not significantly correlated with the residual fraction (r=0.205) or the clearance half-time of the early component (r=0.138) of¹¹C-labeled palmitate as a marker of β-oxidation of the fatty acid.

Conclusions

These data indicate that, although the myocardial uptake of BMIPP may not directly reflect β-oxidation of fatty acids, its uptake may reflect both regional myocardial blood flow and fatty acid extraction.     

Prognostic value of fatty acid imaging in patients with angina pectoris without prior myocardial infarction: comparison with stress thallium imaging

A fatty acid analogue, ¹²³I-labelled -methyl iodophenyl pentadecanoic acid (BMIPP), has been used to identify ischaemic and metabolically impaired myocardium. However, the prognostic value of BMIPP imaging, particularly in relation to stress myocardial perfusion imaging, remains unclear. Data from 167 consecutive patients with angina pectoris but without prior myocardial infarction (MI) who had undergone both BMIPP and stress ²⁰¹Tl (sTL) imaging were analysed. Tracer uptake was graded using a 13-segment, 4-point scoring model. Patients were followed up for 48 months with primary end points (cardiac death, non-fatal MI) as hard cardiac events and with secondary end points (late revascularisation, recurrent angina and heart failure) as soft events. For overall cardiac events (5 hard and 29 soft events), Kaplan-Meier analysis revealed significantly lower event rates in subgroups with normal BMIPP uptake, a summed difference score of sTL (SDS) of <3 or absence of diabetes mellitus when compared to each counterpart. Multivariate Coxs analysis revealed reduced BMIPP uptake, SDS 3, diabetes and reduced ejection fraction to be significant predictors. Negative predictive values of normal BMIPP and SDS <3 for all events were 91% and 84%, respectively. No hard event occurred in 66 patients with normal BMIPP uptake, whereas two patients with SDS <3 but impaired BMIPP uptake had hard events. In conclusion, normal BMIPP imaging is an excellent prognostic sign, independently of stress myocardial perfusion imaging, in patients with angina pectoris without prior MI.     

Factors affecting myocardial 2-[F-18]fluoro-2-deoxy-d-glucose uptake in positron emission tomography studies of normal humans

The goal of this study was to identify the anatomic and physiologic factors affecting left ventricular myocardial 2-[F-18]fluoro-2-deoxy-d-glucose (FDG) uptake and myocardial glucose utilization rates (MRGlc) in normal humans. Eighteen healthy male volunteers were studied in the fasting state (4–19 h) and 16 after oral glucose loading (100 g dextrose) with positron emission tomography (PET) and FDG. Substrate and hormone concentrations were measured in each study. The kinetics of myocardial FDG uptake were evaluated using both a three-compartment model and Patlak graphical analysis. Systolic blood pressures and rate pressure products were similar in the fasting and postglucose states. MRGlc averaged 0.24±0.17 mol/min/g in fasting subjects and rose to 0.69±0.11 mol/min/g after glucose loading. Phosphorylation rate constant, k₃, and MRGlc were linearly related (P < 0.001). Increases in MRGIc following glucose loading were correlated with plasma glucose, insulin and free fatty acid concentrations, ratios of insulin to glucagon levels, and influx rate constants of FDG. Glucose loading improved the diagnostic image quality due to more rapid clearance of tracer from blood and higher myocardial FDG uptake. When MRGlc, glucose and insulin concentrations, and insulin to glucagon ratios exceeded 0.2 mol/min/g, 100 mg/dl, 19 U/ml, and 0.2 U/pg, respectively, myocardial uptake of FDG was always adequate for diagnostic use. FDG image quality and MRGlc were similar after relatively short (6 ±2 h) and overnight (16 ± 2 h) fasting. Significant (P<0.05) regional heterogeneity of myocardial FDG uptake and MRGlc was observed in both the fasting and the postglucose studies. MRGlc and FDG uptake values in the posterolateral wall were higher than those in the anterior wall and septum. Thus, both 6-h and overnight fasts resulted in similarly low myocardial glucose utilization rates. While MRGlc and myocardial FDG uptake depended on plasma glucose, free fatty acid, and insulin concentrations, the results also suggest an additional dependency on plasma glucagon levels. Regional heterogeneities in myocardial FDG uptake and MRGlc are evident and independent of the subjects' dietary state. These regional heterogeneities need to be considered in studies of patients with cardiac disease.Laboratory of Biomedical and Environmental Sciences operated for the US Department of Energy by the University of California under Contract DE-FC03-87ER60615Correspondence to: Y Choi     

Prognostic value of iodine-123 labelled BMIPP fatty acid analogue imaging in patients with myocardial infarction

This study was undertaken to evaluate the prognostic value of iodine-123 labelled 15-iodophenyl3-R,S-methyl pentadecanoic acid (BMIPP) imaging in patients with myocardial infarction. BMIPP is an iodinated methyl branched fatty acid analogue which is trapped in the myocardium with little washout, thereby reflecting fatty acid utilization in the myocardium. We previously reported that in patients with myocardial infarction, regions are often observed where reduced BMIPP uptake is seen relative to thallium-201 perfusion at rest. However, the clinical significance of such discordant BMIPP uptake remains unknown. Fifty consecutive patients with chronic myocardial infarction referred for stress thallium scan and coronary arteriography underwent BMIPP imaging at rest. Each patient was in a stable condition at the time of the radionuclide study. Follow-up was performed at a mean interval of 23 months to investigate the prognostic implications of the radionuclide studies. Nine patients had cardiac events during the follow-up period. Univariate analysis showed that the number of discordant BMIPP versus²⁰¹TL uptake segments was the best predictor of future cardiac events (P=0.0245), followed by the presence of discordant BMIPP uptake (P=0.0388) and the number of²⁰¹TL redistribution segments (P=0.0444). When all the clinical and radionuclide variables were analysed by Cox regression analysis, the presence of discordant BMIPP uptake was the best, and an independent, predictor of future cardiac events (²=8.5) followed by the number of coronary stenoses on angiography (²=3.9). These preliminary data suggest that decreased BMIPP uptake relative to²⁰¹TL is a valuable predictor of future cardiac events in patients with myocardial infarction. Areas with such discordant BMIPP uptake may contain jeopardized myocardium where fatty acid utilization has been severely suppressed relative to myocardial perfusion.Presented in part at the 40th Annual Meeting of Society of Nuclear Medicine at Orlando, Florida, June 1994     

Beta-oxidation of 1-[14C]-17-[131I]-iodoheptadecanoic acid following intracoronary injection in humans results in similar release of both tracers

Radioiodine labelled 17-iodo-heptadecanoic acid (IHA) is used for non-invasive study of myocardial metabolism in coronary heart disease and cardiomyopathy. Yet in the interpretation of in vivo myocardial tracer kinetics, it is controversial whether the intracellular degradation of IHA or the removal of iodide across cellular membranes is the rate-limiting step in iodide release from the myocardium. In five patients undergoing coronary sinus catheterization, a mixture of about 40 kBq of [¹²³I] NaI was injected into the left coronary artery. During the following 15-min period, frequent blood samples were taken from the aorta and the coronary sinus. In the aqueous phase of the venous blood, ¹⁴CO₂ and inorganic ¹³¹I appeared nearly in parallel, with a peak time of 4–5 min. Moreover, as shown by the AV difference, there was no significant back diffusion of IHA and no significant non-specific deiodination detectable over the period of observation. There was myocardial retention of inorganic iodide (¹²³I) injected into the left coronary artery. The data strongly support the premise that lipid turnover through -oxidation is the rate-limiting step in the externally measured release of iodide after IHA injection, provided that recirculating inorganic radioactive iodide is corrected for. In addition, 15 volunteers were studied using [¹¹C]palmitic acid and [¹²³I]IHA using PET and dynamic planar camera scintigraphy with iodide correction. There was no significant difference between the mean values of the elimination half-times, and also no significant correlation between half-times of both fatty acids for single individuals.     

Characterization of IMPY as a potential imaging agent for β-amyloid plaques in double transgenic PSAPP mice

Deposition of -amyloid (A) plaques in the brain is likely linked to the pathogenesis of Alzheimers disease (AD). Developing specific A aggregate-binding ligands as in vivo imaging agents may be useful for diagnosis and monitoring the progression of AD. We have prepared a thioflavin derivative, 6-iodo-2-(4-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, IMPY, which is readily radiolabeled with ¹²⁵I/¹²³I for binding or single-photon emission computerized tomography (SPECT) imaging studies. Characterization of [¹²⁵I]IMPY binding to plaque-like structures was evaluated in double transgenic PSAPP mice. [¹²⁵I]IMPY labeled A plaques in transgenic mouse brain sections, and the labeling was consistent with fluorescent staining and A-specific antibody labeling. Significant amounts of A plaques present in the cortical, hippocampal, and entorhinal regions of the transgenic mouse brain were clearly detected with [¹²⁵I]IMPY via ex vivo autoradiography. In contrast, [¹²⁵I]IMPY showed little labeling in the age-matched control mouse brain. Tissue homogenate binding further corroborated the A plaque-specific distribution in various brain regions of transgenic mouse, and correlated well with the known density of A deposition. Using a tissue dissection technique, [¹²⁵I]IMPY showed a moderate increase in the cortical region of transgenic mice as compared to the age-matched controls. In vitro blocking of [¹²⁵I]IMPY by carrier observed via autoradiography in mouse brain sections was not replicated by an in vivo blocking experiment in living TT mouse brain. The failure was most likely due to a significant carrier effect, which slows down the tracer in vivo metabolism, leading to an increased brain uptake. Taken together, these data indicate that [¹²³I]IMPY is a potentially useful SPECT imaging agent for in vivo labeling of A plaques in the living brain.     

Time-course of ”redistribution” of thallium-201 administered during transient ischemia

The redistribution of Tl-201 administered as a single dose during treadmill exercise and monitored by external imaging may permit differentiation between transient ischemia and old myocardial infarction. The time course of this redistribution of Tl-201 was examined in 20 closed chest dogs instrumented with indwelling left atrial catheters and occlusive cuffs placed around the proximal left circumflex coronary artery. In 15 of the dogs Tl-201 and Sr-85 microspheres (15) were injected during transient coronary artery occlusion: Five of the dogs were sacrificed 2 min later without releasing the occlusion; five dogs were sacrificed after 30 min and five dogs after 4 h of reperfusion. Five dogs with permanent occlusion of the left circumflex coronary artery were studied 4 h after Tl-201 administration. Compared to normal myocardium Tl-201 activity in regions with>95% flow reductions was decreased by 93.3% in the five dogs sacrificed 2 min after administration. After 30 min of reperfusion this difference was 59.7% and was only 16.5% after 4 h of reperfusion. During the initial 30 min of reperfusion this change in regional distribution was due to a 22% fall in activity in normal myocardium and a 4.4 fold increase in the transiently ischemic myocardium. Activity in normal myocardium declined further by 63% from 30 to 240 min of reperfusion while activity in the transiently ischemic myocardium decreased by 15.5%, although this change was statistically not significant. Thus, early redistribution of Tl-201 reflects active uptake of Tl-201 by transiently ischemic tissue and decrease in Tl-201 activity in normal myocadium. During late reperfusion redistribution is primarily due to a more rapid loss of Tl-201 from normal myocardium. We conclude that transient ischemia is visualized best early after stress. Imaging begun late after exercise, e.g., after 30 min, may not permit differentiation between transient ischemia and old myocardial infarction.Dr. Schuler is a recipient of a Fulbright Travel Grant and a grant from the Heinrich-Hertz Foundation, Duesseldorf, GermanyThis project was supported by Specialized Center of Research on Ischemic Heart Disease, NIH Research Grant HL-17682 by the National Heart, Lung and Blood Institute     

A comparison between terminally radioiodinated hexadecenoic acid (125I-HA) and heptadecanoic acid (131I-H0A) in the dog heart

The regional myocardial distribution of ¹²⁵I-16-iodo-9-hexadecenoic acid (¹²⁵I-HA) and ¹³¹I-17-iodo-heptadecanoic acid (¹³¹I-H⁰A) was determined in one normal dog and in five dogs within 5 min after coronary artery occlusion. The total myocardial uptake of ¹²⁵I-H A was about 40% lower than that of ¹³¹I-H⁰A. The ratio ¹²⁵I:¹³¹I in the normally perfused parts of the myocardium was 0.38–0.81, but the ischemic tissue showed a higher ¹²⁵I:¹³¹I-¹³¹I ratio (0.87–1.03), due to lower accumulation of ¹³¹I-H⁰A in ischemic myocardium. We conclude that both radioiodinated fatty acids are reliable indicators of myocardial perfusion and that iodo-heptadecanoic acid, when labeled with ¹²³I, may be preferred to iodo-hexadecenoic acid as the labeled fatty acid for cardiac imaging agent in clinical practice.     

Effect of 3-methyl-branching on the metabolism in rat hearts of radioiodinated iodovinyl long chain fatty acids

The metabolism of two new 3-methyl-branched iodovinyl fatty acids in rat hearts was evaluated by determining the subcellular and lipid pool distribution of these radiolabeled analogues after intravenous injection. Methyl branching had been introduced into the straight chain analogue, 19-iodo-18-nonadecenoic acid (IVN), to produce the monomethyl analogue, 19-iodo-3-(R,S)-methyl-18-nonadecenoic acid (BMIVN) and the dimethyl derivative, 19-iodo-3,3-dimethyl-18-nonadecenoic acid (DMIVN) in the hope of inhibiting beta oxidation. Since the presence of 3-methyl branching results in delayed myocardial clearance in rats, differences were sought in the lipid and subcellular distribution of these branched analogues that might correlate with the prolonged retention and reflect differences in metabolism. Hearts of rats injected intravenously with the radiolabeled fatty acids were removed and homogenized and the homogenates partitioned between the chloroform-methanol (organic) fraction and the aqueous fraction. Comparison of the distribution of radioactivity between the organic and aqueous fractions showed that most of the DMIVN and BMIVN activity was in the organic fraction with IVN activity initially divided equally between the two fractions. Identification of the lipid components of these organic fractions showed that there was slow incorporation of DMIVN into the triglyceride and polar lipid fractions with a slow loss from the free fatty acid fraction. With the straight chain IVN analogue which shows rapid washout from rat hearts, there was loss of activity from all 3 lipid components during the 60 min. The monomethyl branched BMIVN analogue demonstrated predominant storage in the polar lipid fraction with some incorporation into triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)