Radioiodinated tracers for myocardial imaging

Recent advances in the efficient production of high purity radioiodine (123I) and new efficient radiolabeling techniques have allowed the development of new classes of cardiovascular radiopharmaceuticals. These include 123I-labeled fatty acids to assess myocardial metabolism, 123I-metaiodobenzylguanidine (MIBG) for myocardial neuronal activity, labeled monoclonal antibodies for myocardial necrosis, and labeled lipoproteins for receptor concentration. 123I-labeled fatty acids and MIBG are under clinical investigation with encouraging results. 123I- and 111In-labeled fragments of monoclonal antibodies to myosin have been used for imaging myocardial necrosis in humans. The development of radiotracers for imaging of cholinergic and adrenergic receptors is still in the experimental stage. Recent advances in imaging instrumentation and radiopharmaceuticals have resulted in cardiac imaging applications beyond blood pool ventriculography, perfusion, and infarct-avid imaging. Developments of radioiodine (123I)-labeled agents promise to play an important role in the assessment of myocardial metabolism, neuronal activity, and receptor concentration. The chemistry of iodine is well defined compared with that of 99mTc; therefore, iodine isotopes are well suited for labeling biologically important molecules. Among the iodine isotopes, 123I has nearly ideal nuclear properties for nuclear medical applications with a 13.3-hour half-life (T1/2) and 159 keV gamma emission (83%). Despite the nearly ideal chemical and nuclear properties of 123I, the widespread application of 123I-based radiopharmaceuticals in clinical practice has been limited by high production costs (123I is produced in a cyclotron), relatively limited availability, and the presence of undesirable radionuclidic impurities (124I, T1/2 = 4.2 days; 125I, T1/2 = 60 days; 126I, T1/2 = 13.1 days). The relatively long T1/2 and beta particle emission can substantially increase the higher radiation burden to the patient. High energy gamma rays (greater than 600 KeV) from these impurities can degrade images obtained using low energy collimators. Recent developments in production techniques have greatly reduced the levels of the undesirable radionuclides in 123I. Ready availability of pure 123I at modest cost, in concentrations suitable for the radio-labeling of a variety of useful biomolecules, should enhance the clinical applications of 123I-labeled compounds. Molecules labeled with 123I that are useful in cardiac imaging studies are fatty acid analogs, monoclonal antibodies, receptor binding agents, and norepinephrine analogs. This article will discuss developments in radioiodine (123I)-labeled radiotracers for myocardial imaging.     

Radioiodinated biotin derivatives for in vitro radioassays

The synthesis of two radioiodinated biotin derivatives with the biotin-ureido group intact is described. This synthesis was performed by coupling (pH 8.5, 20-22 degrees C, 90 min) N-hydroxysuccinimidobiotin to tyramine, which was radioiodinated prior to this using a modified chloramine-T method. Two derivatives were produced, the N-[beta-(4-OH-3-125I-phenyl)ethyl] and the N-[beta-(4-OH-3,5-di 125I-phenyl)ethyl] biotin amides, depending on the amount of tyramine used in the radioiodination reaction. The final products were separated by thin layer chromatography (n-butanol: 2N NH4OH: ethanol, 3:1:1, v/v/v). The radioiodinated derivatives that were synthesized or their resulting mixture were found to complete with biotin for the avidin-binding sites; thus, they were capable of being used as tracers in biotin radioassays. The specific activity of their mixture was high-greater than 350 Ci/mmol-and they were stable for 2 mo at 4 degrees C.     

Radioiodinated branched-chain fatty acids: substrates for beta oxidation? Concise communication

Branched-chain iodinated fatty acids have been proposed for use as myocardial imaging agents. Several omega- iodoalkyl and omega- iodoaryl beta-methyl branched fatty acids have been synthesized and tested in rats. Myocardial activity levels at t = 5 min are affected by chain length for both alkyl and aryl acids, with chain lengths of 16 carbons possessing higher levels of activity than shorter lengths. Branching significantly lowers heart-to-blood ratios relative to straight-chain analogs. The degree of branching also affects radioactivity levels. Monoalkylation at the beta-carbon does not reduce the levels for omega- iodoalkyl fatty acids, but dialkylation reduces the levels significantly. Branching in the omega- iodoaryl series of fatty acids altered the time course of activity in the myocardium from a level of activity decreasing with time for the straight-chain acid to an essentially constant level of activity for the branched analogs.     

The effect of beta blocker withdrawal on adenosine myocardial perfusion imaging

Background

The effect of beta blockers on myocardial blood flow (MBF) under vasodilators has been studied in several SPECT and PET myocardial perfusion imaging (MPI) studies with divergent results. The present study evaluated the effect of a beta blocker withdrawal on quantitative adenosine MBF and on MPI results.

Methods

Twenty patients with beta blockers and CAD history were studied with quantitative adenosine N-13 ammonia PET. The first study was performed under complete medication and the second after beta blocker withdrawal. The PET studies were independently read with respect to MPI result and clinical decision making.

Results

Global MBF showed an increase from 180.2 ± 59.9 to 193.6 ± 60.8 mL·minute^?1/100 g (P = .02) after beta blocker withdrawal. The segmental perfusion values were closely correlated (R ² = 0.82) over the entire range of perfusion values. An essentially different interpretation after beta blocker discontinuation was found in two cases (10%).

Conclusion

A beta blocker withdrawal induces an increase in adenosine MBF. In the majority of cases, MPI interpretation and decision making are independent of beta blocker intake. If a temporary beta blocker withdrawal before MPI is not possible or was not realized by the patient, it is appropriate to perform adenosine stress testing without loss of the essential MPI result.     

Radioiodinated endothelin-1: a radiotracer for imaging endothelin receptor distribution and occupancy

Endothelin (ET) is one of the most potent vasoconstrictors known. Recently, ET has been implicated in various diseases, e.g., acute renal failure and congestive heart failure, which present the possibility of treating such diseases with endothelin receptor antagonists. However, establishing the dosages for these antagonists may be difficult because no convenient physiologic indicator of action exists, and because of complexities in receptor function. Two receptor subtypes have been identified for which selective antagonists have been reported (e.g., BQ-123 for the ETA receptor and BQ-788 for the ETB receptor). Of the three natural peptide hormones (ET-1, ET-2, and ET-3), ET-1 exhibits high affinity for both subtypes of receptor. Using the selective peptide antagonists, and a nonpeptide antagonist with relatively balanced affinity for the two subtypes (L-749,329), we have characterized the interactions of [125I]ET-1 with its receptors in vivo (in rat). BQ-123, BQ-788, and L-749,329 inhibited binding consistent with binding to a single receptor site. However, the sum of inhibition by the selective antagonist was greater than 100% (as defined by inhibition with L-749,329), which suggests (a) lower in vivo selectivity than determined in vitro and/or (b) receptor subtype interactions. The latter explanation is supported, in part, by in vitro autoradiographic studies as well as studies in isolated tissues and cells. We synthesized ET-1 labeled with I-123 and obtained images of receptor distribution in both rat and rhesus monkey and have demonstrated our ability to visualize, via planar, noninvasive imaging, the occupancy of endothelin receptor by antagonists in both kidney and lung. [123I]ET-1 can therefore be used to determine clinical dosages of antagonist needed for receptor saturation.     

Nitrate-augmented myocardial imaging for assessment of myocardial viability

²⁰¹Tl myocardial perfusion imaging is presently done by several possible strategies. Stress/delayed redistribution, stress/redistribution/reinjection, and rest/redistribution imaging can be useful in the clinical assessment of myocardial viability. Unfortunately, the extent of myocardial viability may still be underestimated even by ²⁰¹Tl reinjection imaging, compared with ¹⁸F-fluorodeoxyglucose positron emission tomography. ^99mTc-labeled sestamibi imaging provides results similar to those of ²⁰¹Tl imaging in the detection of coronary artery disease, but several previous studies suggest that stress/rest ^99mTc-labeled sestamibi imaging significantly underestimates myocardial viability. Recently it has been reported that the administration of nitrates, before ²⁰¹Tl reinjection, improves detection of defect reversibility. Several studies also suggested that administration of nitrates before the injection of ^99mTc-labeled sestamibi significantly improved detection of reversibility with this agent, whereas additional studies showed further that this combination improves the predictive accuracy for recovery of left ventricular function and perfusion after coronary revascularization, compared with a standard rest ^99mTc-labeled sestamibi study. Nitrate administration before the injection of ²⁰¹Tl and ^99mTc-labeled sestamibi may thus be a potentially attractive alternative for the evaluation of myocardial viability. Although the available results are encouraging, further studies are needed to evaluate the clinical value of ²⁰¹Tl and ^99mTc-labeled sestamibi imaging, in combination with nitrates, for predicting recovery of left ventricular dysfunction.     

Radioiodinated diacylglycerol analogue: a potential imaging agent for single-photon emission tomographic investigations of cerebral ischaemia

Phospholipid metabolism is closely related to membrane perturbation in cerebral ischaemia. We investigated in vivo topographical lipid metabolism using an iodine-123-labelled diacylglycerol analogue, (1-(15-(4-iodine-123-iodophenyl)-pentadecanoyl)-2-stearoyl-rac-glycerol) (¹²³I-labelled DAG), in a middle cerebral artery (MCA) occlusion model with the aim of positive imaging of ischaemic insult. Sprague-Dawley rats underwent coagulation of the MCA to induce permanent occlusion. MCA occlusion times prior to injection of¹²³I-labelled DAG ranged from 15 min to 14 days. Each rat was injected with 11–37 MBq of¹²³I-labelled DAG via a tail vein. After 30 min, in vivo autoradiographs were reconstructed. Scanning of the living rat brain in this MCA occlusion model was performed using a gamma camera with a pinhole collimator. Cerebral infarctions were recognized in the frontal cortex, the parietal cortex and the lateral portion of the caudate-putamen by 2,3,5-triphenyltetrazolium hydrochloride staining. In infarcted regions (region 1),¹²³I-labelled DAG incorporation showed a slight decrease up to 12 h; it then increased up to 6 days and decreased thereafter. In peri-infarcted regions (region 2), the incorporation showed almost no change up to 12 h, then increased up to 5–6 days and decreased thereafter. In other regions (region 3), the incorporation showed no change. Lipid analysis showed that¹²³I-labelled DAG was metabolized to 15-(4-iodine-123-iodophenyl)-pentadecanoic acid by DAG lipase and to¹²³I-labelled phosphatidylcholine. Scanning of the ischaemic region showed higher accumulation than on the non-lesioned side. We established a method to visualize ischaemic foci as positive images. The early changes in¹²³I-labelled DAG incorporation were closely related to DAG lipase, which degraded the accumulated intrinsic DAG, and increased¹²³I-labelled DAG incorporation in the chronic stage involves several aspects of neural destruction in the process of autolysis. It is concluded that the reported method could have a clinical future.     

Fatty acids for myocardial imaging

Radioiodinated free fatty acids are tracers that can be used to assess both myocardial perfusion and metabolism. There have been several fatty acids and structurally modified fatty acids studied since Evans' initial report of radiolabeled I-123 oleic acid in 1965. The radiolabeling of a phenyl group added to the long chain fatty acids in the omega-terminal position opposite the carboxyl terminal group prevents nonspecific deiodination and the rapid release of free iodine as the tracer undergoes beta-oxidation. The additional inclusion of a methyl or dimethyl group to the chain slows oxidation resulting in prolonged myocardial retention. The longer retention of the radiolabel permits longer image acquisitions more compatible with single photon emission computed tomography (SPECT) imaging, especially with single-detector imaging systems. Several protocols have been implemented using these compounds, particularly 15-(para-iodophenyl)-3-R,S-methyl pentadecanoic BMIPP, to detect abnormal fatty acid metabolism in ischemic heart disease as well as in nonischemic and hypertrophic cardiomyopathies. Successful management of patients with ischemic cardiomyopathies depends on the accurate identification of hibernating myocardium. The studies covered in this review suggest that both IPPA and BMIPP, especially when combined with markers of myocardial perfusion, may be excellent tracers of viable and potentially functional myocardium. Future studies with larger numbers of patients are needed to confirm the results of these studies and to compare their efficacy with that of other available imaging modalities. Cost and distribution issues will have to be resolved for these metabolic tracers to compete in the commercial marketplace. Otherwise they will likely be available only on a limited basis for research use. As progress is made with these issues and with the development of newer imaging systems, the use of radioiodinated and fluorinated fatty acids is likely to be increasingly attractive.     

Radiopharmaceuticals for imaging myocardial perfusion

A replacement for 201Tl used in myocardial perfusion imaging with a 99mTc-labeled complex is a long-sought goal. Now, at least three varieties of 99mTc-complexes are being made available for clinical studies. This review summarizes the development of these agents and presents basic research data accumulated in this area. Also, relevant clinical radiopharmaceutical protocols and relative merits of competing 99mTc-agents are discussed.     

Technical aspects of myocardial SPECT imaging.

Myocardial perfusion SPECT imaging accounts for well over 90% of all myocardial perfusion imaging performed in the United States today. Although clearly superior to the traditional planar technique in terms of image contrast and consequent diagnostic and prognostic yield, the SPECT approach also involves additional acquisition and processing steps. This article concisely describes the entire technical sequence of myocardial SPECT imaging, from the acquisition of projection images to their filtration and tomographic reconstruction and concluding with reorientation of the tomographic transaxial images. A simplified explanation of the frequency, or Fourier, domain and the operation of digital filters is also presented to help the reader intuitively understand these important concepts.     

Cardiac 123 I-MIBG imaging and clinical variables in risk stratification in patients with heart failure treated with beta blockers

Both myocardial m-[123I]iodobenzylguanidine (123I-MIBG) uptake and plasma norepinephrine are markers of sympathetic activation in heart failure and have been shown to portend a poorer prognosis. However, these observations were noted before treatment with beta blockers became part of standard clinical practice. Fifty-eight patients with chronic heart failure (New York Heart Association functional class II and III, ejection fraction <35%; 53% ischaemic cardiomyopathy) were prospectively studied with a mean follow-up of 36 months. During the observational period, 17 patients (29.3%) had a predefined event (death and heart transplantation). All prognostic parameters were obtained before beta blocker therapy was initiated. In both uni- and multivariate analysis, the heart-mediastinum ratio of 123I-MIBG uptake did not correlate with cardiovascular mortality. In the multivariate Cox regression analysis, plasma norepinephrine, peak oxygen consumption, end-diastolic volume as measured by echocardiography and exercise performance during bicycling and walking had prognostic significance in patients with heart failure treated with beta blockers in addition to angiotensin-converting enzyme inhibitors.     

Optimized spiral imaging for measurement of myocardial T2 relaxation.

Microcirculation oxygen levels and blood volumes should be reflected in measurements of myocardial T(2) relaxation. This work describes the optimization of a spiral imaging strategy for robust myocardial T(2) measurement to minimize the standard deviation of T(2) measurement (sigmaT(2)). Theoretical and experimental studies of blurring at muscle/blood interfaces enabled the derivation of parameter sets which reduce sigma T(2) to the level of 5%. T(2) relaxation mapping within healthy volunteers provided estimation of residual sigmaT(2) within the optimized technique. The standard deviation in T(2) measurement across regions of interest (ROIs) in different locations is about 9%. The standard deviation in T(2) measurement in an ROI across different time points is about 5%.     

A hand-held beta imaging probe for FDG

Objectives

Advances in radiopharmaceuticals and clinical understanding have escalated the use of intraoperative gamma probes in surgery. However, most probes on the market are non-imaging gamma probes that suffer from the lack of ancillary information of the surveyed tissue area. We have developed a novel, hand-held digital Imaging Beta Probe? (IBP?) to be used in surgery in conjunction with beta-emitting radiopharmaceuticals such as ¹⁸FDG, ¹³¹I and ³²P for real-time imaging of a surveyed area with higher spatial resolution and sensitivity and greater convenience than existing instruments.

Methods

We describe the design and validation of a hand-held beta probe intended to be used as a visual mapping device to locate and confirm excision of ¹⁸FDG-avid primary tumors and metastases in an animal model.

Results

We have demonstrated a device which can generate beta images from ¹⁸FDG avid lesions in an animal model.

Conclusions

It is feasible to image beta irradiation in animal models of cancer given ¹⁸FDG. This technology may be applied to clinical mapping of tumors and/or their metastases in the operating room. Visual image depiction of malignancy may aid the surgeon in localization and excision of lesions of interest.     

Gated 99Tcm-MIBI myocardial function imaging.

The introduction of the 99Tcm isonitrile perfusion agents has provided improved myocardial image quality with conventional imaging equipment allowing improved edge definition on gating. We evaluated left ventricular wall motion in 46 patients using gated 99Tcm-2-methoxy-2-methyl-isopropyl-1-isonitrile (MIBI) scintigraphy. Using a method of myocardial profiles in four axes, global and regional fractional shortening (FS) were assessed. A good correlation was found between FS in the left anterior oblique (LAO) 40 degrees projection and ejection fraction (EF) on gated radionuclide ventriculography (r = 0.81, P less than 0.001). This was improved by using FS in two planes, LAO 40 degrees and anterior (r = 0.88, P less than 0.001). There was also a good correlation between FS in two planes and EF on cine-angiography (r = 0.72, P less than 0.001). There was good intra- and interobserver agreement with the studies. Assessment of myocardial function using gated MIBI imaging and myocardial profiles provides useful additional information to the perfusion scan, thus enhancing the diagnostic usefulness of the agent.     

A novel approach to multipinhole SPECT for myocardial perfusion imaging.

Myocardial perfusion imaging with SPECT remains critically important for diagnosing, assessing, and evaluating treatment of coronary artery disease. However, conventional rotational SPECT suffers from prolonged study times because of relatively low detection efficiency. We therefore have investigated a multipinhole collimator that could improve the detection efficiency in cardiac SPECT by a factor 5, while providing image quality comparable to standard rotational SPECT techniques using parallel-hole collimation. METHODS: We have measured the spatial resolution and efficiency of a 9-pinhole and a parallel-hole collimator mounted to a standard nuclear medicine gamma-camera as a function of distance from the collimator with a point source array. The efficiency was derived by integrating the detected counts, and the spatial resolution was determined from the full width at half maximum of the detected point spread function. In addition, we generated and reconstructed projection data of a 9-pinhole collimator from a digital heart phantom with a basal lesion. We simulated 3 scenarios: single view from left anterior, 2 views from left anterior and left lateral; and 4 views that include the 2 previous views and left lateral and anterior views. RESULTS: We found that the spatial resolution of the 9-pinhole collimator with 8-mm diameter pinholes was 30% poorer than that for the parallel-hole collimator, whereas the detection efficiency was increased by >10-fold. This predicts that a 9-pinhole collimator having the same spatial resolution as a parallel-hole collimator will have 5 times greater efficiency. Reconstructed data from 1 angular view of the 9-pinhole collimator showed the expected loss of spatial resolution in the longitudinal direction with reduced resolution of the basal lesion. In addition, the tomograms showed distortions in the apical region. In contrast, the reconstructed data from 2 and 4 views of the 9-pinhole collimator demonstrated good lesion definition and also produced images describing the shape and size of the heart more accurately. CONCLUSION: Our results indicate that myocardial multipinhole tomography with 2 or more views offers an image quality and spatial resolution comparable with current rotational SPECT techniques, but with the advantage of a 5-fold increase in efficiency.     

Cationic complexes of technetium for myocardial imaging

Over the past 15 years a major goal of research in cardiovascular nuclear medicine has been the development of 99mTc complexes that could replace 201Tl and thus enhance the utility of myocardial perfusion imaging. This paper presents an overview of the current state-of-art of the development of cationic 99mTc complexes for this purpose. Cationic 99mTc complexes that have been evaluated as myocardial perfusion imaging agents in human volunteers and/or animals are discussed and classified on the basis of the oxidation state of the technetium center.