Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

Measles Edmonston vaccine strain derivatives have potent oncolytic activity against osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumor affecting children and young adults, and development of metastatic disease is associated with poor prognosis. The purpose of this study was to evaluate the antitumor efficacy of virotherapy with engineered measles virus (MV) vaccine strains in the treatment of OS. Cell lines derived from pediatric patients with OS (HOS, MG63, 143B, KHOS-312H, U2-OS and SJSA1) were infected with MV expressing green fluorescent protein (MV-GFP) and MV-expressing sodium iodide symporter (MV-NIS) strains. Viral gene expression and cytotoxicity as defined by syncytial formation, cell death and eradication of cell monolayers were demonstrated. Findings were correlated with in vivo efficacy in subcutaneous, orthotopic (tibial bone) and lung metastatic OS xenografts treated with the MV derivative MV-NIS via the intratumoral or intravenous route. Following treatment, we observed decrease in tumor growth of subcutaneous xenografts (P=0.0374) and prolongation of survival in mice with orthotopic (P<0.0001) and pulmonary metastatic OS tumors (P=0.0207). Expression of the NIS transgene in MV-NIS infected tumors allowed for single photon emission computed tomography and positron emission tomography-computed tomography imaging of virus infected tumors in vivo. Our data support the translational potential of MV-based virotherapy approaches in the treatment of recurrent and metastatic OS.

Pilot comparison of F-fluorocholine and F-fluorodeoxyglucose PET/CT with conventional imaging in prostate cancer.

INTRODUCTION: Conventional imaging (CI) is known to have limitations with respect to staging of patients with primary or relapsed prostate cancer. Positron emission tomography/computed tomography (PET/CT) with (18)F-flurodeoxyglucose (FDG) is also often suboptimal because of low tracer avidity, but (18)F-fluorocholine (FCH) appears to be a promising alternative molecular imaging probe. We report a prospective pilot study of PET/CT comparing both tracers for staging and restaging of patients with prostate cancer. METHODS: Sixteen prostate cancer patients were evaluated (7 for staging and 9 for restaging). All patients also underwent CI, comprising at least an abdominopelvic CT and a bone scan. All imaging results and other relevant data were extracted from the imaging reports and medical charts. RESULTS: Based on all imaging-detected disease sites, both FCH-PET/CT and FDG-PET/CT (79%) were more sensitive than CI (14%), with the highest number of sites of nodal and distant disease on FCH PET/CT. FCH-PET/CT alone would have provided sufficient clinical information to form an appropriate management plan in 88% of cases, as compared with 56% for CI. CONCLUSION: FCH-PET/CT has the potential to impact on the management of patients with prostate cancer significantly more often than CI.

Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers.

UNLABELLED: Elevated levels of choline (trimethyl-2-hydroxyethylammonium) and choline kinase (CK) activity in neoplasms have motivated the development of positron-labeled choline analogs for noninvasive detection of cancer using PET. The aim of this study was to further evaluate [(18)F]fluorocholine (fluoromethyl-dimethyl-2-hydroxyethylammonium [FCH]) as an oncologic probe in comparison with several other closely related molecules. METHODS: FCH, [(18)F]fluoromethyl-methylethyl-2-hydroxyethylammonium (FMEC), [(18)F]fluoroethyl-dimethyl-2-hydroxyethylammonium (FEC), and [(18)F]fluoropropyl-dimethyl-2-hydroxyethylammonium (FPC) were synthesized through [(18)F]fluoroalkylation reactions. In vitro phosphorylation rates of the (18)F-labeled choline analogs and [methyl-(14)C]choline (CH) were studied using yeast CK. Several choline radiotracers were also evaluated in cultured PC-3 human prostate cancer cells. Data on chemical stability, radiation dosimetry, and toxicity of FCH were obtained. PET studies with FCH were performed on a patient with prostate cancer and a patient with a brain tumor. RESULTS: FCH and FMEC revealed in vitro phosphorylation by CK that was similar to that of choline, whereas rates of phosphorylation of FEC and FPC were 30% (P < 0.01) and 60% (P < 0.01) lower, respectively. Accumulations of FCH, CH, and FPC in cultured PC-3 cancer cells were comparable, whereas uptake of FEC was approximately one fifth that of FCH. Dosimetry estimates using FCH biodistribution data in mice indicated that the kidneys are radiation-dose-critical organs for FCH. PET images of a patient with recurrent prostate cancer showed uptake of FCH in the prostatic bed and in metastases to lymph nodes. FCH PET showed uptake in malignancies in a patient with metastatic breast cancer. PET revealed FCH uptake in biopsy-proven recurrent brain tumor with little confounding uptake by normal brain tissues. CONCLUSION: The fluoromethyl choline analog FCH may serve as a probe of choline uptake and phosphorylation in cancer cells, whereas fluoroethyl (FEC) and fluoropropyl (FPC) analogs appear to have relatively poorer biologic compatibility. Preliminary PET studies on patients with prostate cancer and with breast cancer and brain tumor support further studies to evaluate the usefulness of FCH as an oncologic probe.

Is chronically dysfunctional yet viable myocardium distal to a severe coronary stenosis hypoperfused?

BACKGROUND: Controversy exists regarding the perfusion status of chronically dysfunctional yet viable myocardium. Studies investigating the pathophysiology of this condition have reached different conclusions, with some suggesting that myocardial blood flow (MBF) in these regions is normal at rest with regional dysfunction resulting from repetitive stress-induced ischemia (stunned myocardium), whereas others have proposed that MBF is chronically reduced at rest (hibernating myocardium). However, adequately powered experimental studies investigating this question in an appropriate animal model using clinically available techniques have not been performed. Based on the mixed results of prior studies, we hypothesized that these chronically dysfunctional yet viable regions may actually represent a mixture of hibernation and stunning. Consequently, the purpose of this study was to quantitatively determine the distribution of MBF in left ventricular regions with chronically impaired resting function but preserved viability in a large population of animals with single-vessel coronary stenosis in an attempt to further elucidate the mechanism(s) responsible for chronic, reversible myocardial dysfunction. METHODS: Fifty-two adult mini-swine with 90% proximal left circumflex (LCx) stenosis underwent dynamic positron emission tomography (PET) with 13N-ammonia and 18F-fluorodeoxyglucose and dobutamine stress echocardiography (DSE) (5 to 40 microg/kg/min) 1 month after stenosis creation. Values of MBF and FDG uptake by PET and wall motion score index (WMSI) by DSE were compared using a standard 16-segment model. RESULTS: Of 312 possible LCx segments seen on PET, 303 (97.1%) were visualized by DSE. Of the 303 LCx segments, 279 (92.1%) had rest dysfunction (WMSI > or = 2) by DSE. One hundred eighty-two segments (60.1%) had decreased (< 85% reference) MBF at rest with preserved to increased (> 60% reference) FDG uptake and were classified as hibernating. Ninety-two segments (30.4%) had preserved MBF (> or = 85% reference) and were classified as stunned. Five segments (1.7%) with reduced (< or = 60% reference) FDG uptake by PET and akinesis or dyskinesis at rest (WMSI > or = 3) and no contractile reserve were considered infarcted. Hibernating segments had significantly higher FDG uptake at rest (360.7+/-48.3 vs 212.3+/-17.7% septal values; p < 0.001) than stunned segments consistent with greater resting ischemia. Likewise, mean rest WMSI was also worse in hibernating versus stunned segments (2.35+/-0.04 vs 2.13+/-0.04; p < 0.001). There was no difference in the percentage of hibernating versus stunned segments exhibiting contractile reserve during dobutamine infusion (55.5 vs 63.7%; p = 0.4), indicating similar degrees of viability. CONCLUSIONS: Myocardial hibernation and stunning appear to frequently coexist in regions served by a stenotic coronary vessel. Hibernating regions appear to have greater resting ischemia based on higher values of FDG uptake and greater resting dysfunction. Reversible left ventricular dysfunction in the setting of chronic coronary artery disease is likely due to a combination of these two mechanisms.

Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure.

BACKGROUND: Use of beta-adrenoreceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial oxygen consumption and an improvement in myocardial energy efficiency. One potential mechanism for this beneficial effect is a shift in myocardial substrate use from increased free fatty acid (FFA) oxidation to increased glucose oxidation. METHODS AND RESULTS: We studied the effect of carvedilol therapy on myocardial FFA and glucose use in 9 patients with stable New York Heart Association functional class III ischemic cardiomyopathy (left ventricular ejection fraction

An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in Patients with Congestive Heart Failure.

UNLABELLED: Understanding the metabolic consequences of heart failure is important in evaluating potential mechanisms for disease progression and assessing targets for therapies designed to improve myocardial metabolism in patients with heart failure. PET is uniquely suited to noninvasively evaluate myocardial metabolism. In this study, we investigated the kinetics of 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) and [18F]FDG in patients with stable New York Heart Association functional class III congestive heart failure and a left ventricular ejection fraction of no more than 35%. METHODS: Twelve fasting patients underwent dynamic PET studies using [18F]FTHA and FDG. From the dynamic image data, the fractional uptake rates (Ki) were determined for [18F]FTHA and FDG. Subsequently, serum free fatty acid and glucose concentrations were used to calculate the myocardial free fatty acid and glucose uptake rates, respectively. Uptake rates were compared with reported values for [18F]FTHA and FDG in subjects with normal left ventricular function. RESULTS: The average Ki for [18F]FTHA was 19.7 +/- 9.3 mL/100 g/min (range, 7.2-36.0 ml/100 g/min). The average myocardial fatty acid use was 19.3 +/- 2.3 mmol/100 g/min. The average Ki for FDG was 1.5 +/- 0.37 mL/100 g/min (range, 0.1-3.3 mL/100 g/min), and the average myocardial glucose use was 12.3 +/- 2.3 mmol/100 g/min. CONCLUSION: Myocardial free fatty acid and glucose use in heart failure can be quantitatively assessed using PET with [18F]FTHA and FDG. Myocardial fatty acid uptake rates in heart failure are higher than expected for the normal heart, whereas myocardial glucose uptake rates are lower. This shift in myocardial substrate use may be an indication of impaired energy efficiency in the failing heart, providing a target for therapies directed at improving myocardial energy efficiency.

Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: initial findings in prostate cancer.

The up-regulation of rates of choline uptake and phosphorylation in certain malignancies has motivated the development of positron-labeled choline analogues for noninvasive detection of cancer using positron emission tomography (PET). The choline analogue, no-carrier-added [18F]fluoromethyl-dimethyl-2-hydroxyethyl-ammonium (FCH), was synthesized through the intermediate [18F]fluorobromomethane. FCH was evaluated in relationship to 2-[18F]fluoro-2-deoxyglucose (FDG) as an oncological probe in cultured PC-3 human prostate cancer cells, a murine PC-3 human prostate cancer xenograft model, and in PET imaging studies of patients with prostate cancer. FCH was synthesized in 20-40% radiochemical yield and >98% radiochemical purity. Accumulation of FCH and FDG were comparable in cultured prostate cancer cells, whereas only FCH was inhibited (90%) by hemicholinium-3, a specific inhibitor of choline transport and phosphorylation. FCH showed similar biodistribution to [14C]choline in the tumor-bearing mouse, with prominent renal and hepatic uptake. Tumor uptake of FCH was similar to choline and FDG in the mouse model, although tumor:blood ratios were moderately higher for FCH. Initial PET imaging studies in prostate cancer patients showed high uptake of FCH in advanced prostate carcinoma and detection of osseous and soft tissue metastases. FCH uptake by tumors was markedly reduced in patients rescanned during androgen deprivation therapy. It is concluded that FCH closely mimics choline uptake by normal tissues and prostate cancer neoplasms. FCH is potentially useful as a PET tracer for detection and localization of prostate cancer and monitoring effects of therapy.

Preliminary evaluation of 15-[18F]fluoro-3-oxa-pentadecanoate as a PET tracer of hepatic fatty acid oxidation.

UNLABELLED: The liver is an important site of fat oxidation. Abnormalities of hepatic mitochondrial fatty acid oxidation (HMFAO) are associated with obesity, type II diabetes, alcoholic hepatitis, and nonalcoholic steatohepatitis. Noninvasive assessment of HMFAO by PET has been impeded by the lack of a specific radiotracer. METHODS: No-carrier-added 15-[18F]fluoro-3-oxa-pentadecanoate (FOP) was synthesized and evaluated in living rats and isolated rat livers. RESULTS: FOP showed high uptake and slow clearance of radioactivity from livers in living rats. Inhibition of HMFAO by pretreatment of fasting rats with the carnitine palmitoyltransferase-I (CPT-I) inhibitor reduced the liver-to-blood ratio by 64%. In isolated rat livers, perfused in normoxic (95% O2) and hypoxic (15% O2) conditions with glucose (5 mmol/L) and palmitate (0.15 mmol/L), the externally measured kinetics of FOP showed reversible binding in tissue. The kinetics were adequately fit by a catenary 2-compartment model for estimation of tracer distribution volumes (DVs). The DVs of both compartments were found to correlate with fractional palmitate oxidation rate (FPOR) in experiments in normoxic and hypoxic conditions. The correlation was particularly strong for the slower second compartment (DV2 [mL/g dry weight] = 34.1 FPOR [mL/min/g dry weight] - 0.7, r = 0.89). Relatively small levels of diffusible metabolites of FOP were formed in vivo and in isolated rat liver. CONCLUSION: The selective uptake of FOP by liver and the high sensitivity of hepatic FOP DV to changes of HMFAO with CPT-I inhibition and hypoxia suggests potential usefulness for the 3-oxa fatty acid analog in assessments of hepatic mitochondrial oxidation of exogenous fatty acids with PET. These data emphasize that further studies are required to clarify the intracellular disposition of FOP in the liver and test its validity as a tracer of HMFAO over a broad range of conditions.

Induction of angiogenesis after TMR: a comparison of holmium: YAG, CO2, and excimer lasers.

BACKGROUND: Transmyocardial laser revascularization (TMR) is an emerging treatment for end-stage coronary artery disease. A variety of lasers are currently available to perform the procedure, although their relative efficacy is unknown. The purpose of this study was to compare changes in myocardial blood flow and function 6 months after TMR with holmium:yttrium-aluminum-garnet (holmium:YAG), carbon dioxide (CO2), and xenon chloride excimer lasers in a model of chronic ischemia. METHODS: Miniswine underwent subtotal (90%) left circumflex coronary stenosis. Baseline positron emission tomography and dobutamine stress echocardiography were performed to document hibernating myocardium in the left circumflex coronary artery distribution. Animals were then randomized to sham redo-thoracotomy (n = 5) or TMR using a holmium:YAG (n = 5), CO2 (n = 5) or excimer (n = 5) laser. Six months postoperatively, the positron emission tomography and dobutamine stress echocardiography studies were repeated and the animals sacrificed. RESULTS: In animals undergoing TMR with holmium: YAG and CO2 lasers, a significant improvement in myocardial blood flow to the lased left circumflex regions was seen. No significant change in myocardial blood flow was seen in sham- or excimer-lased animals. There was a significant improvement in regional stress function of the lased segments 6 months postoperatively in animals undergoing holmium:YAG and CO2 laser TMR that was consistent with a reduction in ischemia. There was no change in wall motion in sham- or excimer-lased animals. Significantly greater neovascularization was observed in the holmium:YAG and CO2 lased regions than with either the sham procedure or excimer TMR. CONCLUSIONS: Transmyocardial laser revascularization with either holmium:YAG or CO2 laser improves myocardial blood flow and contractile reserve in lased regions 6 months postoperatively. These changes were not seen following excimer TMR or sham thoracotomy, suggesting that differences in laser energy or wavelength or both may be important in the induction of angiogenesis.

An experimental model of chronic myocardial hibernation.

BACKGROUND: Hibernating myocardium describes persistently impaired ventricular function at rest caused by reduced coronary blood flow. However, a realistic animal model reproducing this chronic ischemic state does not exist. The purpose of this study was to explore whether chronic low-flow hibernation could be produced in swine. METHODS: Miniswine underwent 90% stenosis of the left circumflex coronary artery. Positron emission tomography and dobutamine stress echocardiography were performed 3 and 30 days (n = 6) or 14 days (n = 4) after occlusion to evaluate myocardial blood flow and viability. Triphenyl tetrazolium chloride assessed percent infarction. Electron microscopy was used to identify cellular changes characteristic of hibernating myocardium. RESULTS: Positron emission tomography (13N-labeled-ammonia) 3 days after occlusion demonstrated a significant reduction in myocardial blood flow in the left circumflex distribution. This reduced flow was accompanied by increased glucose use (18F-fluorodeoxyglucose), which is consistent with hibernating myocardium. Thirty days after occlusion, positron emission tomography demonstrated persistent low flow with increased glucose use in the left circumflex distribution. Dobutamine stress echocardiography 3 days after occlusion demonstrated severe hypocontractility at rest in the left circumflex region. Regional wall motion improved with low-dose dobutamine followed by deterioration at higher doses (biphasic response), findings consistent with hibernating myocardium. The results of dobutamine stress echocardiography were unchanged 30 days after occlusion. Triphenyl tetrazolium chloride staining (n = 6) revealed a mean of 8% +/- 2% infarction of the area-at-risk localized to the endocardial surface. Electron microscopy (n = 4) 14 days after occlusion demonstrated loss of contractile elements and large areas of glycogen accumulation within viable cardiomyocytes, also characteristic of hibernating myocardium. CONCLUSIONS: Chronic low-flow myocardial hibernation can be reproduced in an animal model after partial coronary occlusion. This model may prove useful in the study of the mechanisms underlying hibernating myocardium and the use of therapies designed to improve blood flow to the heart.

Synthesis and preliminary evaluation of (18)F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation.

Interest remains strong for the development of a noninvasive technique for assessment of regional fatty acid oxidation rate in the myocardium. (18)F-labeled 4-thia palmitate (FTP, 16-[(18)F]fluoro-4-thia-hexadecanoic acid) has been synthesized and preliminarily evaluated as a metabolically trapped probe of myocardial fatty acid oxidation for positron emission tomography (PET). The radiotracer is synthesized by Kryptofix 2.2.2/K(2)CO(3) assisted nucleophilic radiofluorination of an iodo-ester precursor, followed by alkaline hydrolysis and by purification by reverse phase high performance liquid chromatography. Biodistribution studies in rats showed high uptake and long retention of FTP in heart, liver, and kidneys consistent with relatively high fatty acid oxidation rates in these tissues. Inhibition of carnitine palmitoyl-transferase-I caused an 80% reduction in myocardial uptake, suggesting the dependence of trapping on the transport of tracer into the mitochondrion. Experiments with perfused rat hearts showed that the estimates of the fractional metabolic trapping rate (FR) of FTP tracked inhibition of oxidation rate of palmitate with hypoxia, whereas the FR of the 6-thia analog 17-[(18)F]fluoro-6-thia-heptadecanoic acid was insensitive to hypoxia. In vivo defluorination of FTP in the rat was evidenced by bone uptake of radioactivity. A PET imaging study with FTP in normal swine showed excellent myocardial images, prolonged myocardial retention, and no bone uptake of radioactivity up to 3 h, the last finding suggesting a species dependence for defluorination of the omega-labeled fatty acid. The results support further investigation of FTP as a potential PET tracer for assessing regional fatty acid oxidation rate in the human myocardium.

Tracer kinetic modeling in nuclear cardiology.

The introduction of tracer kinetic modeling techniques in conjunction with nuclear imaging has allowed the assessment of physiologic processes in the myocardium in a noninvasive and quantitative manner. Alongside the development of novel radiopharmaceuticals for both positron emission tomography and single photon emission computed tomography is the clarification of their pharmacology, pharmacokinetics, and modeling strategies for assessment of physiologic rates from imaging data. Image analysis and tracer kinetic modeling techniques used in nuclear cardiology must address unique considerations related to the heart. The most commonly used tracers and modeling techniques are presently discussed, with particular attention given to methods that allow absolute quantitation of physiologic processes. The applications of these techniques are obvious in research protocols and may find more use in future clinical studies.

Regional cerebral blood flow and depersonalization after tetrahydrocannabinol administration.

OBJECTIVE: The aim of this study was to examine the relationship between depersonalization induced by tetrahydrocannabinol (THC), and regional brain activation. METHOD: Cerebral blood flow (CBF) was measured by means of positron emission tomography (PET) in 59 normal right-handed volunteers before and following intravenous infusions of THC. RESULTS: After THC, CBF showed a global increase which was more marked in the right hemisphere, frontal lobes and anterior cingulate. CONCLUSION: Regression analyses showed positive correlations between the right frontal and anterior cingulate and depersonalization.

Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium.

BACKGROUND: Transmyocardial laser revascularization (TMR) has been demonstrated effective for relieving angina, although prior studies have yielded inconsistent results regarding postoperative myocardial perfusion and function. This study evaluated long-term changes in myocardial perfusion and contractile reserve after TMR in a model of hibernating myocardium. METHODS: Miniswine had subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, positron emission tomography and dobutamine stress echocardiography were performed to document ischemic, viable (hibernating) myocardium in the left circumflex distribution. Animals then had sham redo thoracotomy (n = 4) or TMR (n = 6). Six months later the positron emission tomography and dobutamine stress echocardiography studies were repeated. RESULTS: Myocardial blood flow in the left circumflex distribution as measured by positron emission tomography was significantly reduced in all animals after 2 weeks in the low-flow state. In animals that had TMR, there was significant improvement in myocardial blood flow to the lased regions 6 months postoperatively. No significant change in myocardial blood flow was seen in sham animals at 6 months. Dobutamine stress echocardiography after 2 weeks of low-flow demonstrated severe hypocontractility at rest in the left circumflex region of all animals, with a biphasic response to dobutamine consistent with hibernating myocardium. In animals that had TMR, there was a trend toward improved resting function and significantly improved regional stress function in the lased segments 6 months postoperatively, consistent with a reduction in ischemia. Global left ventricular wall motion at peak stress improved significantly as well. There was no change in wall motion 6 months postoperatively in sham-operated animals. CONCLUSIONS: This study found improvements in myocardial perfusion and regional and global contractile reserve 6 months after TMR in a porcine model of hibernating myocardium. This improved perfusion and function likely accounts for the clinical benefits of the procedure.

Iodopyridine-for-iodobenzene substitution for use with low molecular weight radiopharmaceuticals: application to m-iodobenzylguanidine.

Substituting a pyridine ring for a benzene ring in the acylation agent N-succinimidyl 3-iodobenzoate has resulted in a useful approach for the radiohalogenation of monoclonal antibodies, peptides, and labeled biotin conjugates. It was hypothesized that such a substitution in m-iodobenzylguanidine (MIBG), a radiotracer used in the detection and treatment of neuroendocrine tumors, might result in an analogue with more rapid normal tissue clearance, thereby facilitating its use for tumor therapy. For the preparation of this analogue, 3-guanidinomethyl-5-iodopyridine (GMIP; 9b), the silicon precursor 4 was synthesized starting from 5-bromonicotinic acid. Attempts to convert 4 to 9b under various conditions were not successful. Radioiodinated 9b could be prepared by the iododestannylation of the tin precursor 8 in 65-70% radiochemical yield. A number of in vitro, in vivo, and ex vivo studies showed that pyridine-for-benzene substitution in MIBG yielded a compound that no longer was taken up by the uptake-1 pathway.

Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia.

UNLABELLED: To study the sensitivity of two fatty acid tracers to changes in beta-oxidation, the myocardial retention kinetics of 125I-iodine-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) and 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) were compared in states of oxygen deprivation due to ischemia and hypoxia. METHODS: Nineteen swine were studied by extracorporeal perfusion of the three coronary arteries. Fatty acid beta-oxidation rates were determined by infusion of tritiated palmitate into the left anterior descending artery (LAD) and by measurement of labeled water production in the LAD perfusion bed. After a baseline period of 30 min, animals were divided into three groups and subjected to a 50-min intervention period. For the control group, there was no change in perfusion; for the ischemia group, there was a 60% decrease in LAD perfusion; and for the hypoxia group, the perfusion rate was unchanged, but venous blood was used as the LAD perfusate. Continuous infusion of FTHA and BMIPP into the LAD started 10 min into the intervention period and continued until the end of the intervention period. Retention rates of the two tracers were compared between the LAD and circumflex perfusion beds. RESULTS: No difference in beta-oxidation rate occurred from the baseline to the intervention period in the control group. A 50% reduction in beta-oxidation occurred in the ischemia group, and an 80% reduction occurred in the hypoxia group. No difference in retention of BMIPP or FTHA occurred in the control group. In the ischemia group, reduction in retention of both tracers occurred. However, in the hypoxia group, FTHA uptake was unchanged, whereas BMIPP retention increased compared to the circumflex arterial bed. CONCLUSION: Decreased retention of both BMIPP and FTHA occurred with ischemia, despite the known differences in metabolism of the two tracers. This difference in metabolism was further highlighted in the setting of hypoxia with increased BMIPP uptake. Thus, these results suggest that uptake of both FTHA and BMIPP tracks reduction of fatty acid utilization in myocardial ischemia but fails in tracking reduction of fatty acid oxidation during hypoxia.

Myocardial uptake of the fatty acid analog 14-fluorine-18-fluoro-6-thia-heptadecanoic acid in comparison to beta-oxidation rates by tritiated palmitate.

UNLABELLED: The fatty acid tracer 14-18F-fluoro-6-thia-heptadecanoic acid (FTHA) is a metabolically trapped tracer of exogenous fatty acid utilization. The objectives of this study were to determine the relationship of FTHA uptake to changes in perfusion and fatty acid oxidation and to confirm the retention of FTHA in the mammalian heart. METHODS: Six pigs with extracorporeal perfusion of the left anterior descending artery (LAD) and cannulation of the LAD vein were studied. The extraction fraction (EF) of FTHA, measured from LAD arterial and venous blood samples, was compared to beta-oxidation rates, determined by water production from tritiated palmitate. After a baseline period, changes in FTHA EF were measured in 15-min periods of hyperemia, control (baseline flow rate) and lactate infusion. After the lactate infusion, FTHA infusion was terminated, and a 15-min washout period was observed. RESULTS: Beta-oxidation rate was unchanged from the baseline period during the hyperemic and control periods. With lactate infusion, the expected myocardial preference for lactate was noted, with a decline in exogenous fatty acid oxidation. Fluorine-18-FTHA EF paralleled the changes in beta-oxidation, with a decrease in EF during lactate infusion. Increase in perfusion was associated with a decrease in FTHA EF, compared to control, such that the product of flow and extraction was maintained. A linear relationship of FTHA EF to fractional tritiated water production was found. Washout analysis confirmed minimal washout of tracer at 15 min after termination of infusion. Organic solvent extraction of tissue samples suggested that the majority of tissue radioactivity was protein-bound. CONCLUSION: In the extracorporeally perfused mammalian heart, FTHA EF declined during suppression of beta-oxidation with lactate infusion and alteration in perfusion without change in fatty acid oxidation rate. The linear relationship of FTHA EF with fractional water production from tritiated palmitate further confirms a correlation of the uptake of FTHA with fatty acid beta-oxidation rate and supports the utility of FTHA in the noninvasive determination of fatty acid oxidation rate. Furthermore, the trapped nature of the tracer may allow the use of graphical analysis for the quantification of beta-oxidation rates.

Quantification of myocardial perfusion by MRI after coronary occlusion.

The objectives of this study were to define the relationship between the first order constant of Gd-DTPA transfer (K1) and the myocardial blood flow (MBF) at rest and to compare it with an equivalent relationship obtained for positron emission tomography (PET). In a canine model of permanent coronary occlusion (n = 4), myocardial and blood time concentration curves obtained by 13N-ammonia PET and Gd-DTPA-enhanced MRI were fitted by a one-compartment model to determine K1. A linear relationship was observed between MRI-derived K1 and MBF measured by microspheres (K1 = 0.88 x flow -0.015, R = 0.95), which compares favorably with the equivalent relationship derived from PET (K1 = 0.74 x flow +0.16, R = 0.88). The results of this preliminary study suggest that, at rest and distal to a permanently occluded coronary artery, myocardial perfusion quantification by MRI is possible and can challenge PET.

Transcapillary transport of metaiodobenzylguanidine (MIBG) in isolated rat heart.

A better understanding of transcapillary transport for tracer metaiodobenzylguanidine (MIBG) is desirable for development of tracer kinetic models that yield meaningful estimates of neuronal uptake function from tissue radioactivity time courses. This study utilized a multiple-indicator approach in Langendorff-perfused rat hearts to define transport mechanisms and determine the capillary permeability-surface area (PSc) over a broad range of flow (F). Multiple injections within the same heart at different flows allowed characterization of the PSc/F relationship within the same heart. The coefficient of variation of E for multiple injections within the same hearts at constant flow was 6 +/- 2% (3 to 6 injections in 9 hearts). In 10 hearts (4 to 6 injections per heart), flow was varied between 2.0-16.5 mL/min. PSc was found to be nearly proportional to flow in each heart (r = 0.88 +/- 0.14; slope = 0.23 +/- 0.10; intercept = 11 +/- 7 mL/min/g dry). Tissue hypoxia at low flows, as evidenced by enhanced lactate production, did not appear to influence the PSc/F relationship. Pharmacologic blockade of uptake-1 and uptake-2 had negligible affect on E or PSc as compared with flow-matched controls, although tissue retention was markedly reduced. The results show PSc of MIBG to be nearly proportional to flow but independent of specific neuronal and extraneuronal transport mechanisms and tissue hypoxia. The results are consistent with a passive diffusion process across the capillary endothelial barrier. The increase in PSc with increasing flow could reflect capillary recruitment and/or enhanced capillary permeability.