A comparison between terminally radioiodinated hexadecenoic acid (*I-HA) and 201Tl-thallium chloride in the dog heart

The regional myocardial distribution of ¹³¹I-16-iodo-9-hexadecenoic acid (¹³¹I-HA) and ²⁰¹Tl-thallium chloride (²⁰¹TlCl) was determined in normal dogs and after occlusion of a coronary artery. The uptake of ¹³¹I-HA was about 20% lower than that of ²⁰¹TlCl but the ratio ²⁰¹Tl/¹³¹I was the same for the whole myocardium within narrow limits for normal as well as infarcted tissue. The potential of ¹²³I-HA as a radiopharmaceutical for diagnosis of myocardial defects is discussed.Dept. Internal Medicine, Head Prof. Dr. C. van der MeerDept. Cardiology, Head Prof. Dr. J.P. RoosDept. Physiology, Head Prof. Dr. A.A. Knoop     

External detection of regional myocardial metabolism with radioiodinated hexadecenoic acid in the dog heart

In a previous study we have demonstrated that terminally iodinated hexadecenoic acid (¹³¹I-HA) and Thallium-201 (²⁰¹Tl) are comparable in myocardial uptake and distribution in the ischemic dog heart (Westera et al. 1980). In the present study the potential value of ¹³¹I-HA was proved in determining regional myocardial metabolism in 19 dog experiments.In ten dogs, ¹³¹I-HA was administered 5 min after occlusion of a coronary artery (group II), in six dogs after a 90 min occlusion period (group III). Three dogs served as controls (group I). The turnover rates (t1/2) of ¹³¹I-HA were calculated from mono-exponential time-activity curves, obtained by external detection over ischemic and normally perfused areas during a 30 min period after IV injection of 0.7–1.5 mCi ¹³¹I-HA. The t1/2 values in ischemic regions were found to be significantly longer (group II, 25.1±2.6 min; group III, 22.6±1.8 min) than in nonischemic areas (group II, 12.5±1.8 min; group III, 14.2±1.4 min). The t1/2 values in the control dogs (group I, 13.4±1.4 min) were not significantly different from the turnover rates in the non-ischemic areas of the occluded hearts.We conclude that the study of turnover rates of radioiodinated free fatty acids allows the determination of regional myocardial metabolism and offers a means to distinguish normally perfused from ischemic myocardial tissue.     

Influence of propranolol on uptake of radioiodinated heptadecanoic acid and thallium-201 in the dog heart

In an experimental study, the influence of propranolol on myocardial uptake of radioiodinated heptadecanoic acid (¹³¹I-HDA) and thallium-201 (²⁰¹Tl) in the dog heart was assessed. Uptake of ¹³¹I-HDA and ²⁰¹Tl was evaluated in ten control dogs and in ten dogs 20 min after IV administration of propranolol (0.15 mg/kg). In both groups, four healthy dogs were studied and six dogs were studied after coronary artery occlusion. It was shown that both total uptake of ¹³¹I-HDA and ²⁰¹Tl did not alter significantly, regardless of significant changes in hemodynamic parameters and total arterial plasma FFA levels. However, distribution of both ¹³¹I-HDA and ²⁰¹Tl was markedly affected by propranolol, since the endocardial to epicardial ratio showed significantly higher values in the ischemic myocardial regions. The results of our study indicate that propranolol (1) preserves myocardial perfusion in the normal and acutely ischemic dog heart, and (2) gives a more favorable distribution in the ischemic myocardial region towards the subendocardial layers.     

Dual tracer autoradiographic study of beta-methyl-(1-14C) heptadecanoic acid and 15-p-(131I)-iodophenyl-beta-methylpentadecanoic acid in normotensive and hypertensive rats

The myocardial distribution of 15-p-[131I]iodophenyl-3-(R,S)-methylpentadecanoic acid (BMPDA) and 1[14C]-3-(R,S)-methylheptadecanoic acid (BMHDA) was compared in normotensive and hypertensive rats using quantitative dual tracer autoradiographic techniques. The myocardial distribution of carbon-14 [14C] BMHDA and iodine-131 [131I] BMPDA was nearly homogeneous in the normotensive rats, while both tracers showed similar, though very heterogeneous, distribution in hypertensive hearts with decreased uptake in the endocardial region. Our data demonstrate that myocardial distribution of [131I]BMPDA was essentially the same as [14C]BMHDA, and thus single photon emission computed tomographic imaging with 123I-labeled BMPDA could be useful for the detection of regional changes of myocardial fatty acid uptake in patients with prolonged and severe hypertension.     

Effect of doxorubicin on [omega-I-131]heptadecanoic acid myocardial scintigraphy and echocardiography in dogs

The effects of serial treatment with doxorubicin on dynamic myocardial scintigraphy with [omega-I-131]heptadecanoic acid (I-131 HA), and on global left-ventricular function determined echocardiographically, were studied in a group of nine mongrel dogs. Total extractable myocardial lipid was compared postmortem between a group of control dogs and doxorubicin-treated dogs. A significant and then progressive fall in global LV function was observed at a cumulative doxorubicin dose of 4 mg/kg. A significant increase in the myocardial t1/2 of the I-131 HA was observed only at a higher cumulative dose, 10 mg/kg. No significant alteration in total extractable myocardial lipids was observed between control dogs and those treated with doxorubicin. Our findings suggest that the changes leading to an alteration of myocardial dynamic imaging with I-131 HA are not the initiating factor in doxorubicin cardiotoxicity.     

I-123 heptadecanoic acid — value and limitations in comparison with C-11 palmitate

To define the potential of ¹²³I-labeled heptadecanoic acid (IHA) for the noninvasive assessment of myocardial free fatty acid (FFA) metabolism, the kinetics of IHA were compared to those of physiologic ¹¹C-palmitate (CPA). The single-pass myocardial extraction fraction of IHA was lower than that of CPA (0.53±0.11 vs 0.65±0.10 under control conditions). Following an intracoronary injection of IHA and CPA, the myocardial time-activity curves showed biphasic clearance of both tracers. While, for CPA, the half-time of the early phase of the time-activity curve was a function of myocardial oxygen consumption (MVO₂), this phase was not found to reflect the oxidative metabolism of IHA. However, for both tracers, the size of the early phase increased with augmented MVO₂, whereas the size of the late phase decreased. The late phase represents storage of both tracers in triglycerides and phospholipids. Hence, while quantitative measurement of CPA oxidation is possible from the early phase of the time-activity curve, only the ratio between the size of the early and late phase might be of value in assessing myocardial FFA metabolism using IHA.

     

Radioimmunoassay of progesterone in crude serum extracts using tritiated and (125I) radioiodinated tracers

Two progesterone-tyraminyl (¹²⁵I) derivatives were prepared from progesterone-11-hemisuccinate and progesterone-3-0(carboxymethyl)oxime, respectively. The analytical performances of these tracers in the progesterone-anti progesterone-11-hemisuccinyl-BSA system were compared with those of tritiated radioligand assumed as a reference. For all of the 11 antisera tested much higher affinity and titers were observed in the case of homologous ¹²⁵I tracer, which however was found to involve drastic sensitivity losses. On the contrary, quite acceptable dose-response curves and affinity and titers close to those related to tritiated progesterone resulted with the heterologous tracer. These results, interpreted in terms of native ligand-tracer competitivity for the antibody sites, led to the choice of the C₃-tyraminyl derivative for the development of a radioimmunoassay method to be compared with the reference tritiated progesterone systems. The two procedures, including minor differences in incubation conditions and B/F separation, were validated for the direct assay of unpurified dried serum extracts. In both cases, satifactory levels of sensitivity, precision and accuracy were proved, the estimates obtained being in a good agreement with data from the literature. On the basis of the present results, some general consideration on the optimization of steroid radioimmunoassay with radioiodinated tracers are tentatively drawn.     

Comparison of 17-iodine-131 heptadecanoic acid kinetics from externally measured time-activity curves and from serial myocardial biopsies in an open-chest canine model

The relation between the externally measured myocardial time-activity curve and the radiochemically determined kinetics of iodine-131(131I) heptadecanoic acid was studied in an open-chest canine model under different metabolic interventions. Kinetics were assessed by analysis of 12 biopsies taken in an assay period of 90 min. Time-activity curves were fitted with a monoexponential plus constant. The halftime value of the exponential of the external curve corresponded well with the elimination rate of 131I from the myocardium: 14.6 +/- 4.5 min vs. 14.6 +/- 5.3 min. The constant was build up of three components: free 131I in cardiac tissue, the almost constant activity of the radiolabeled free fatty acid (FFA) in the myocardial lipid pool, and the radioactivity of blood and noncardiac tissues. The contribution of blood and noncardiac tissue to the constant amounted to a mean value of 77%. These findings support the analysis of externally measured time-activity curves with a monoexponential plus constant curve fit, in which background correction is not necessary. In cases where lipid storage is predominantly present, high T1/2 values, both internally and externally, were found, which were fitted with a monoexponential curve. It can be concluded that externally measured time-activity curves reflect satisfactorily the kinetics of radioiodinated heptadecanoic acid.     

A comparison of scintigraphy with radioiodinated MIBG and CT in localizing pheochromocytomas

In order to define the diagnostic roles of MIBG imaging and CT in the detection of pheochromocytomas (pheos), the results obtained in 45 patients suspected of bearing pheo and studied with both modalities were analyzed and compared. Scintigraphy was correctly negative in 22/23 cases, correctly positive in 11/12 adrenal and 5/5 extra-adrenal pheos, and in 4/5 malignant pheos (metastases present in 2 cases were also identified). CT was correctly negative in 20/23 cases (a mass other than a pheo was detected in 3 patients); correctly positive in 12/12 adrenal and 4/5 extra-adrenal pheos and in 5/5 malignant pheos. Sensitivity, specificity and accuracy of scintigraphy and CT were 91% and 95.4%, 95.6% and 87%, 93.3% and 91.1% respectively (differences were not statistically significant). The overall data emphasize the complementary role of 123/131I-MIBG imaging and CT in the location of pheochromocytomas. A flow-chart essentially grounded on the combined use of both these diagnostic modalities is proposed which includes 123/131I-MIBG scintigraphy as a first choice examination.     

Relative therapeutic efficacy of (125)I- and (131)I-labeled monoclonal antibody A33 in a human colon cancer xenograft.

A33, a monoclonal antibody that targets colon carcinomas, was labeled with (125)I or (131)I and the relative therapeutic efficacy of the 2 radiolabeled species was compared in a human colon cancer xenograft system. METHODS: Nude mice bearing human SW1222 colon carcinoma xenografts were administered escalating activities of (125)I-A33 (9.25-148 MBq) or (131)I-A33 (0.925-18.5 MBq), (125)I- and (131)I-labeled control antibodies, unlabeled antibody, or no antibody. The effects of treatment were assessed using the endpoints of tumor growth delay and cure. RESULTS: Tumor growth delay increased with administered activity for all radiolabeled antibodies. Approximately 4.5 times more activity was required for (125)I-A33 to produce therapeutic effects that were equivalent to those of (131)I-A33. This ratio was approximately 7 for a nonspecific, noninternalizing isotype-matched, radiolabeled control antibody. Unlabeled A33 antibody had no effect on tumor growth. Approximately 10 times more activity of (125)I-A33 produced toxicity similar to that of (131)I-A33, and this ratio fell to approximately 6 for radiolabeled control antibody. CONCLUSION: Treatment with (125)I-A33 resulted in a relative therapeutic gain of approximately 2 compared with (131)I-A33 in this experimental system.     

Diuresis renography. A simultaneous comparison between 131I-hippuran and 99Tcm-MAG3

In 20 patients investigated for unilateral upper urinary tract obstruction diuresis renography was performed simultaneously with 131I-hippuran and 99Tcm-MAG3 using a gamma camera with dual isotope facilities. Furosemide was administered routinely 20 min after radionuclide injection. No significant differences were found in fractional share between the two kidneys, time to maximal activity, residual activity at 20 and 30 min, or rate of emptying after furosemide administration. The MAG3 curves showed, however, better counting statistics and on scintigrams with MAG3 more anatomic details (extent of dilation and site of obstruction) could be seen. It is concluded, that MAG3 is superior to hippuran in the evaluation of patients with possible unilateral upper urinary tract obstruction by diuresis renography.     

Tracer kinetics of 15-(ortho-123/131I-phenyl)-pentadecanoic acid (oPPA) and 15-(para-123/131I-phenyl)-pentadecanoic acid (pPPA) in animals and man

The human myocardium retains oPPA as opposed to pPPA. Therefore turnover of oPPA was compared with that of pPPA in rat hearts and in man, the latter by using substrates double-labeled with 123/131I and 14C. Moreover, substrate binding to coenzyme-A was tested in vitro. In rats, oPPA remained mainly in the pool of free fatty acids, as opposed to pPPA, which was metabolized by mitochondrial beta-oxidation. Binding to coenzyme-A at maximum was 62% for oPPA, 81% for pPPA and 90% for palmitic acid. In man, after i.v. and intracoronary injection of double-labeled oPPA, the two radionuclides reappeared together in venous blood and in coronary sinus respectively, in an unchanged ratio but at a significantly lower rate than with pPPA. It can be concluded that oPPA is bound to coenzyme-A and is retained in the cytosolic lipid pool, while pPPA is metabolized by mitochondrial beta-oxidation. A dual-tracer application of oPPA and pPPA has the potential of being a specific probe for the function of the carnitine shuttle.     

Iodine 131 labelled ioglycamic acid (Biligram) for scintiscanning in hepatobiliary disorders

Iodine-131 labelled Biligram¹ has been evaluated as a radiopharmaceutical for dynamic scintiscanning of the liver and biliary tract. In 10 normal subjects there was good visualisation of the liver and gallbladder. In 18 patients ¹³¹I Biligram was found to be unsatifactory for differentiating parenchymal liver disease from biliary tract obstruction owing to inability to demonstrate the gallbladder when liver function was more than mildly deranged. Quantitative analyses of blood clearance and hepatic activity curves for ¹³¹I Biligram were not clinically helpful. Urinary excretion of ¹³¹I Biligram increased with the degree of hepatic dysfunction.     

Comparison of 16-iodohexadecanoic acid (IHDA) and 15-p-iodophenylpentadecanoic acid (IPPA) metabolism and kinetics in the isolated rat heart

Time courses of radioactivity (residue curves) were obtained following bolus injection into working rat hearts of two ¹²⁵I-labeled long chain fatty acids: 16-iodohexadecanoic acid (IHDA) and 15-p-iodophenylpentadecanoic acid (IPPA). Residue curves were analyzed in terms of a rapid vascular washout component, an early tissue clearance component, and a very slow late component. For IHDA and IPPA in control hearts, early myocardial clearance kinetics were rate limited by the diffusion of catabolites. Sensitivity of the kinetics to impaired fatty acid oxidation was examination by pretreatment of animals with 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). Decreased fatty acid oxidation was indicated in IHDA and IPPA residue curves by a decrease in the relative size of the early clearance component. Analysis of radiolabeled species in coronary effluent and heart homogenates showed that back diffusion of IPPA was slower than that of IHDA; this discrepancy was most apparent in POCA hearts. In vitro binding assays suggested higher tissue: albumin relative affinity for IPPA than for IHDA. Thus, IPPA early clearance kinetics were more closely related to the clearance of labeled catabolite(s) and were therefore more sensitive to the oxidation rate of long chain fatty acids.     

Comparison of 16-iodohexadecanoic acid (IHDA) and 15-p-iodophenylpentadecanoic acid (IPPA) metabolism and kinetics in the isolated rat heart

Time courses of radioactivity (residue curves) were obtained following bolus injection into working rat hearts of two 125I-labeled long chain fatty acids: 16-iodohexadecanoic acid (IHDA) and 15-p-iodophenylpentadecanoic acid (IPPA). Residue curves were analyzed in terms of a rapid vascular washout component, an early tissue clearance component, and a very slow late component. For IHDA and IPPA in control hearts, early myocardial clearance kinetics were rate limited by the diffusion of catabolites. Sensitivity of the kinetics to impaired fatty acid oxidation was examination by pretreatment of animals with 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). Decreased fatty acid oxidation was indicated in IHDA and IPPA residue curves by a decrease in the relative size of the early clearance component. Analysis of radiolabeled species in coronary effluent and heart homogenates showed that back diffusion of IPPA was slower than that of IHDA; this discrepancy was most apparent in POCA hearts. In vitro binding assays suggested higher tissue:albumin relative affinity for IPPA than for IHDA. Thus, IPPA early clearance kinetics were more closely related to the clearance of labeled catabolite(s) and were therefore more sensitive to the oxidation rate of long chain fatty acids.     

A clinical comparison of 99mTc-diethyl-iminodiacetic acid, 99mTc-pyridoxylideneglutamate, and 131I-rose bengal in liver transplant patients.

The relative merits of three radiopharmaceuticals for evaluating liver transplant patients were determined in paired studies. In 86% of studies both 131I-RB and 99mTc-PG gave similar information for differentiation of hepatocellular disease and billary tract obstruction. 99mTc-PG probably demonstrates the biliary tract and small intestine better early after injection (8%); 131I-RB is probably better in showing the colon at 24 hours when intestinal activity is not seen by 1 hour (6%). 99mTc-diethyl-IDA is superior in all respects when compared to 99mTc-PG. The blood retention method (20 min./5 min.) showed that none of the radiopharmaceuticals was a reliable indicator of hepatocyte function when compared to total serum bilirubin.