Experimental Study of a Radiopharmaceutical Agent Based on Modified Fatty Acid Labeled with Technetium-99m.

Using rat model of coronary occlusion, we studied pharmacokinetics and the efficiency of a new radiopharmaceutical agent 99mTc-PDA-DTPA intended for diagnostics of changes in myocardial metabolism and its analogue 123I-PMPDA. 99mTc-PDA-DTPA was eliminated mostly by the kidneys and maximal concentration in the heart was attained within 60 min after intravenous injection; no accumulation in the area of myocardial infarction was observed. The studied substance was inferior to its analogue 123I-PMPDA by the quality of scintigraphic visualization of the heart.

High-performance dendritic contrast agents for X-ray computed tomography imaging using potent tetraiodobenzene derivatives.

The use of computed tomography (CT) for vascular imaging is critical in medical emergencies requiring urgent diagnostic decisions, such as cerebral ischemia and many cardiovascular diseases. Small-molecule iodinated contrast media are often injected intravenously as radiopaque agents during CT imaging to achieve high contrast enhancement of vascular systems. The rapid excretion rate of these agents is overcome by injecting a significantly high dose of iodine, which can have serious side effects. Here we report a simple method to prepare blood-pool contrast agents for CT based on dendrimers for the first time using tetraiodobenzene derivatives as potent radiopaque moieties. Excellent in vivo safety has been demonstrated for these small (13-22nm) unimolecular water-soluble dendritic contrast agents, which exhibit high contrast enhancement in the blood-pool and effectively extend their blood half-lives. Our method is applicable to virtually any scaffold with suitable surface groups and may fulfill the current need for safer, next-generation iodinated CT contrast agents.

Focal impairment in myocardial fatty acid imaging in the left anterior descending artery area, a strong predictor for cardiac death in hemodialysis patients without obstructive coronary artery disease.

PURPOSE: We investigated whether impaired patterns of myocardial fatty acid imaging were associated with cardiac death in dialysis patients without coronary lesions. METHODS: We prospectively enrolled 155 hemodialysis patients without obstructive coronary artery disease, who had been examined by single-photon emission computed tomography (SPECT) using the iodinated fatty acid analogue BMIPP. Uptake of BMIPP on SPECT was graded in 17 segments on a five-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores. Of the enrolled 155 participants, we analyzed 95 who had BMIPP summed scores ≥ 6 (52 men and 43 women, 65 ± 11 years). BMIPP scores ≥ 2 in ≥ 2 consecutive segments in SPECT were defined as focal, and the others as non-focal pattern. RESULTS: Of 95 participants analyzed, 42 (44.2 %) showed focal and 53 (55.8 %) non-focal type. During follow-up for 5.1 ± 2.0 years, 42 died of cardiac events. The occurrence of cardiac death was higher in the focal than in the non-focal group (30/42 [71.4 %] versus 12/53 [22.6 %], p = 0.001). In stepwise Cox hazard analysis, focal pattern was associated with cardiac death (hazard ratio 2.266), independent of impairment of BMIPP SPECT (BMIPP summed scores ≥ 12). The predictive potential of BMIPP SPECT for cardiac death was higher (p < 0.001) in the left anterior descending artery area compared with other coronary territories. CONCLUSIONS: Focal impairment in myocardial fatty acid imaging in the left anterior descending area may strongly predict cardiac death in this population.

Dual pancreas- and lung-targeting therapy for local and systemic complications of acute pancreatitis mediated by a phenolic propanediamine moiety.

To inhibit both the local and systemic complications with acute pancreatitis, an effective therapy requires a drug delivery system that can efficiently overcome the blood-pancreas barrier while achieving lung-specific accumulation. Here, we report the first dual pancreas- and lung-targeting therapeutic strategy mediated by a phenolic propanediamine moiety for the treatment of acute pancreatitis. Using the proposed dual-targeting ligand, an anti-inflammatory compound Rhein has been tailored to preferentially accumulate in the pancreas and lungs with rapid distribution kinetics, excellent tissue-penetrating properties and minimum toxicity. Accordingly, the drug-ligand conjugate remarkably downregulated the proinflammatory cytokines in the target organs thus effectively inhibiting local pancreatic and systemic inflammation in rats. The dual-specific targeting therapeutic strategy may help pave the way for targeted drug delivery to treat complicated inflammatory diseases.

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG.

INTRODUCTION: Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an (18)F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). METHODS: Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with (18)F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [(125)I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. RESULTS: [(18)F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [(18)F]FPOIBG at 2h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [(125)I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The (125)I-labeled congener of FPOIBG gave similar results. On the other hand, [(18)F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [(125)I]MIBG. IC50 values for FPOIBG were higher than those obtained for MIBG and FPOBBG. Unlike the case with [(18)F]FPOBBG, the heart uptake [(18)F]FPOIBG in normal mice was significantly lower than that of MIBG. CONCLUSION: Although [(18)F]FPOIBG does not appear to warrant further consideration as an (18)F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: An (18)F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although (18)F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

Assessment of myocardial metabolic disorder associated with mediastinal radiotherapy for esophageal cancer -a pilot study.

BACKGROUND: To evaluate the dose-effect relations for myocardial metabolic disorders after mediastinal radiotherapy (RT) by performing iodine-123 ß-methyl-iodophenyl pentadecanoic acid (I-123 BMIPP) scintigraphy. METHODS: Between 2011 and 2012, we performed I-123 BMIPP scintigraphy for patients with esophageal cancer before and six months after curative mediastinal RT. Single photon emission computed tomography (SPECT) images of pre-RT and post-RT were registered into RT dose distributions. The myocardium was contoured, and the regional RT dose was calculated. Normalization is required to compare pre- and post-RT SPECT images because the uptake pattern is changed due to the breathing level. Normalization was applied on the mean of SPECT counts in regions of the myocardium receiving less than 5 Gy. Relative values in each dose region (interval of 5 Gy) were calculated on the basis of this normalization for each patient. The reduction in the percent of relative values was calculated. RESULTS: Five patients were enrolled in this study. None of the patients had a past history of cardiac disease. The left ventricle was partially involved in RT fields in all patients. The patients received RT with median total doses of 60-66 Gy for the primary tumor and metastatic lymph nodes. Concomitant chemotherapy consisting of cisplatin or nedaplatin and 5-fluorouracil with RT was performed in 4 patients. All patients had reduced uptake corresponding to RT fields. Dose-effect relations for reduced uptake tended to be observed at 6 months after RT with mean decreases of 8.96% in regions at 10-15 Gy, 12.6% in regions at 20-25 Gy, 15.6% in regions at 30-35 Gy, 19.0% in regions at 40-45 Gy and 16.0% in regions at 50-55 Gy. CONCLUSIONS: Dose-effect relations for myocardial metabolic disorders tended to be observed. We may need to make an effort to reduce high-dose mediastinal RT to the myocardium in RT planning.

Targeting dopamine receptors subtype 2 (D2DR) in pheochromocytomas: head-to-head comparison between in vitro and in vivo findings.

CONTEXT: Dopamine subtype 2 receptors (D2DRs) are overexpressed in pheochromocytomas (PHEOs). D2DR-expressing tumors can be visualized by iodine-123 labeled iodobenzamide (¹²³I-IBZM) single-photon emission computed tomography (SPECT). OBJECTIVE: The hypothesis of this study was that D2DR high expression in PHEOs would allow in vivo visualization through ¹²³I-IBZM SPECT. The present prospective pilot study aims to evaluate the performance of ¹²³I-IBZM SPECT in PHEOs and to correlate the tumor uptake with D2DR expression in tumor samples after surgery. SETTING, MATERIALS, AND METHODS: Ten unrelated patients with PHEOs were evaluated, prior to adrenalectomy, with ¹²³I-IBZM SPECT (whole body scan at 4 and 24 h after the injection; and SPECT centered on the abdomen at 24 h). D2DR mRNA and protein expressions were evaluated in all tumors by quantitative real-time RT-PCR and immunohistochemistry, respectively. MAIN OUTCOME MEASURE: Intensity of tumoral uptake of ¹²³I-IBZM was measured. RESULTS: All PHEOs express D2DR mRNA (ranging from 2.1 to 14.7 copy/copy ß-glucuronidase) and protein (immunostaining score: moderate or strong in 9 of 10 cases). However, none of the patients (0%) showed an increased tumor uptake of ¹²³I-IBZM. CONCLUSIONS: These results suggest that ¹²³I-IBZM is not a useful radiopharmaceutical in the detection and characterization of PHEOs despite D2DR expression. Our findings and data from the related literature may support different hypotheses to explain the failure of D2DR targeting by ¹²³I-IBZM.

Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle.

OBJECTIVE: Fatty acids (FAs) are the major substrate for energy production in the heart. Here, we hypothesize that capillary endothelial fatty acid binding protein 4 (FABP4) and FABP5 play an important role in providing sufficient FAs to the myocardium. APPROACH AND RESULTS: Both FABP4/5 were abundantly expressed in capillary endothelium in the heart and skeletal muscle. The uptake of a FA analogue, 125I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid, was significantly reduced in these tissues in double-knockout (DKO) mice for FABP4/5 compared with wild-type mice. In contrast, the uptake of a glucose analogue, 18F-fluorodeoxyglucose, was remarkably increased in DKO mice. The expression of transcripts for the oxidative catabolism of FAs was reduced during fasting, whereas transcripts for the glycolytic pathway were not altered in DKO hearts. Notably, metabolome analysis revealed that phosphocreatine and ADP levels were significantly lower in DKO hearts, whereas ATP content was kept at a normal level. The protein expression levels of the glucose transporter Glut4 and the phosphorylated form of phosphofructokinase-2 were increased in DKO hearts, whereas the phosphorylation of insulin receptor-ß and Akt was comparable between wild-type and DKO hearts during fasting, suggesting that a dramatic increase in glucose usage during fasting is insulin independent and is at least partly attributed to the post-transcriptional and allosteric regulation of key proteins that regulate glucose uptake and glycolysis. CONCLUSIONS: Capillary endothelial FABP4/5 are required for FA transport into FA-consuming tissues that include the heart. These findings identify FABP4/5 as promising targets for controlling the metabolism of energy substrates in FA-consuming organs that have muscle-type continuous capillary.

Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography.

Preliminary investigation of the radioiodinated (S,S)-reboxetine analogue, (123) I-INER, in baboons showed this tracer to have promise for imaging the noradrenaline transporter (NAT) using single photon emission computed tomography (SPECT). More recently, the radioiodinated (R,S)-stereoisomer of (123) I-INER, (123) I-NKJ64, has been synthesized and preliminary evaluation in rats has been reported. This article reports the brain distribution and pharmacokinetic properties of (123) I-NKJ64 in baboons and compares results with (123) I-INER data in the same species. SPECT studies were conducted in two ovariectomized adult female baboons using two different protocols: (1) bolus of (123) I-INER or (123) I-NKJ64; and (2) bolus plus constant infusion of (123) I-NKJ64 with reboxetine (2.0 mg/kg) administration at equilibrium. Following bolus injection, both radiotracers rapidly and avidly entered the baboon brain. The regional brain accumulation of (123) I-NKJ64 did not match the known distribution of NAT in baboon brain, contrasting with previous results obtained in rats. Conversely, the regional distribution of (123) I-INER was consistent with known distribution of NAT in baboon brain. No displacement of (123) I-NKJ64 was observed following administration of reboxetine. This contrasts with previous data obtained for (123) I-INER, where 60% of specific binding was displaced by a lower dose of reboxetine. These data suggest that (123) I-NKJ64 may lack affinity and selectivity for NAT in baboon brain and (123) I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo.

Accelerated BMIPP uptake immediately after reperfused ischemia in the isolated rat heart model.

OBJECTIVE: 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) can visualize myocardial fatty acid metabolism and has extensive potential for diagnosing cardiac diseases such as acute coronary syndrome in the clinical setting. Increased BMIPP uptake with decreased perfusion occasionally occurs under acute reperfusion ischemia and the kinetics of BMIPP remain unclear. The present study uses the isolated rat heart model to measure kinetic changes in BMIPP under acute reperfusion ischemia. METHODS: Male Wistar rats were allotted to normal control (NG), mild (MG) and severe (SG) ischemia groups. The hearts were perfused according to the Langendorff method at a constant flow rate, and BMIPP wash-in and wash-out were studied. No-flow ischemia was applied for 15 and 30 min to the MG and SG groups, followed immediately by the wash-in and wash-out study. Whole heart radioactivity was determined using an external gamma detector throughout the experiment. Rates of myocardial uptake (K1, mL/min) and clearance (k2, min(-1)) were generated using a compartmental model analysis. The same procedures and protocols were performed using (99m)Tc-sestamibi (MIBI) as a perfusion study. RESULTS: Perfusion pressure significantly increased and mean heart rate significantly decreased in the severe ischemia group (heart rate: 244 ± 76, 304 ± 105 and 94 ± 140 bpm; perfusion pressure: 67 ± 13, 101 ± 31 and 160 ± 84 mmHg for NG, MG and SG, respectively). MIBI-K1 significantly decreased, whereas BMIPP-K1 increased in the MG and SG groups (MIBI-K1: 3.45 ± 1.10, 1.95 ± 0.82, and 1.05 ± 0.13 mL/min; BMIPP-K (1): 3.06 ± 0.88, 3.91 ± 0.87, and 4.94 ± 1.51 mL/min for NG, MG and SG, respectively) with an inverse relationship to the severity of ischemia. MIBI-k2 increased markedly in severe ischemia (NG vs. MG: p < 0.05), whereas BMIPP-k2 did not change in the ischemic groups (MIBI-k2: 0.00072 ± 0.0011, 0.00038 ± 0.00076 and 0.043 ± 0.033; BMIPP-k2: 0.0056 ± 0.0028, 0.0029 ± 0.0010 and 0.0037 ± 0.0022 min(-1) for NG, MG and SG, respectively). CONCLUSION: Myocardial BMIPP uptake increased immediately upon reperfusion after no-flow ischemia, and was inversely related to the severity of ischemia. The increased uptake was not due to reduced clearance, but to accelerated extraction.

¹²³I-NKJ64: a novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain.

Dysregulation of noradrenergic function has been implicated in a variety of psychiatric and neurodegenerative disorders, including depression and Alzheimer's disease. The noradrenaline transporter (NAT) is a major target for antidepressant drugs, including reboxetine, a selective noradrenaline reuptake inhibitor. Therefore, the development of a radiotracer for imaging of the NAT is desirable. In this study, NKJ64, a novel iodinated analog of reboxetine, was radiolabeled and evaluated as a potential single photon emission computerized tomography (SPECT) radiotracer for imaging the NAT in brain. Biological evaluation of the novel radiotracer, ¹²³/¹²5I-NKJ64, was carried out in rats using: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. ¹²5I-NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates (K(D) = 4.82 ± 0.87 nM, mean ± SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of ¹²³I-NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of ¹²³I-NKJ64 in brain, with maximum uptake of 2.93% ± 0.14% (mean ± SEM, n = 3) of the injected dose. The specific to nonspecific ratio (locus coeruleus:caudate putamen) of ¹²³I-NKJ64 uptake measured by ex vivo autoradiography was 2.8 at 30 min post i.v. injection. The prior administration of reboxetine significantly reduced the accumulation of ¹²³I-NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of ¹²³I-NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain.

Cortical and subcortical patterns of I-123 iodobenzamide SPECT in striatal D(2) receptor parkinsonisms.

INTRODUCTION: The D(2) receptor is the most widely expressed dopaminergic receptor in the central nervous system, and it is present at the pre- and postsynaptic dopaminergic regions. It is mainly located in the neostriatum as well as in the globus pallidus, substantia nigra, cerebral cortex, thalamus, etc. The objective of this study was to analyze qualitatively and quantitatively the distribution pattern of the postsynaptic dopamine receptors through SPECT with iodobenzamide (IBZM) in patients with parkinsonism and to determine the benefit of this imaging technique in the differential diagnosis of the parkinsonian syndromes. MATERIALS: A total of 26 patients with clinical and imaging (Iodine-123 fluoropropyl-carbomethoxy-3 beta-(4-iodophenyltropane) [FP-CIT]) diagnostics of parkinsonism, to all of which a study of postsynaptic D(2) receptors with IBZM was made, were retrospectively reviewed. Of total, 12 patients were male (42.85%). The average age was 73 years old (range, 64-83 years). The patients were imaged using SPECT 2 hours after administration of I-123 Iolopride (IBZM) and their images were evaluated qualitatively and quantitatively. To measure the relative density of the D(2) receptors, the studies were registered to a common space in which the structures to be analyzed were delimited over a RM template. Caudate/frontal (C/FI) and putamen/frontal (P/FI) activity indexes were obtained. RESULTS: Of total, 10 patients presented normal IBZM uptake (C/FI of 1.23 + or - 0.13; P/FI of 1.53 + or - 0.11). The 16 studies listed as abnormal were divided into 2 degrees: (I) appearance of thalamic activity with preserved striatal uptake and (II) thalamus and frontal increased uptake with decrease of striatal activity. In the patients with abnormal patterns, the region that showed a greater reduction of uptake was the putamen (P/FI of 1.1 + or - 0.07 for degree 1, P < 0.05 and P/FI of 1.25 + or - 0.19 for degree 2, P < 0.001). For the differential diagnosis of Parkinson disease in relation to the atypical parkinsonisms, the sensitivity was 68.4% (confidence interval, 51.9-87.6) and the specificity was 57.1% (confidence interval, 20.2-88.2). The patients with Parkinson disease with longer evolution times showed a decrease of D(2) activity (3/7). CONCLUSION: The appearance of thalamic activity may be an early indicator of a decrease of D(2) striatal receptors in atypical parkinsonisms and in patients with long-term Parkinson disease.

[Experience with 123I-Iodobenzamide in the differential diagnosis of Parkinson's disease and Parkinson-plus disease]. / Experiencia con 123I-Iodobenzamida en el diagnóstico diferencial de enfermedad de Parkinson frente a Parkinson plus.

OBJECTIVE: To perform a descriptive analysis of the clinical and diagnostic implications of (123)I-IBZM SPECT in the patients studied in our center for movement disorders suggestive of Parkinson-Plus Disease (PP). SUBJECTS AND METHODS: (123)I-IBZM SPECT was performed in 46 patients referred from the movement disorders consultation due to suspicion of PP. According to their symptoms, they were distributed into 3 groups: 35 patients had atypical symptoms (AS) for Parkinson's Disease, 2 showed no response to standard therapy (NR) and 9 presented both factors (AS, NR). The results of SPECT were only assessed qualitatively. RESULTS: The (123)I-IBZM supported the diagnosis of PP in 15(42.9%) out of the 35 patients with AS. The (123)I-IBZM was pathological in one of the two NR patients. Regarding the third group of patients (AS+NR), the (123)I-IBZM was pathological in 6 cases (66.7%). In 95.7% of our sample (44 patients), AS with or without NR was the main factor leading to suspicion of PP and the (123)I-IBZM was altered in only 47.7% (22 patients). Of these 22 cases, the final diagnosis was PP (with high positive predictive value) in 20(91%). CONCLUSION: The study with (123)I-IBZM is useful in the clinical practice because it provides objective diagnostic information with implications for the treatment and prognosis of patients with suspicion of PP.

The washout rate of (123)I-BMIPP and the evolution of left ventricular function in patients with successfully reperfused ST-segment elevation myocardial infarction: comparisons with the echocardiography.

The evolution of the oxidative metabolism of (11)C acetate parallels the recovery of left ventricular(LV) contraction following acute myocardial infarction(AMI). This study was designed to unravel, for the first time, the impact of the global washout rate(WR) of (123)I-beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) on the recovery of LV function followingAMI, as evidenced from conventional echocardiography.Twenty consecutive patients (age: 58 +/- 13 years; 16 males and 4 females) with ST-segment elevation myocardial infarction (STEMI) were enrolled and all of them underwent successful percutaneous coronary intervention (PCI). (123)I-BMIPP cardiac scintigraphy was performed at 7 +/- 3 days after admission. The WR was calculated from the polar map and the regional BMIPP defect score was calculated using a 17 segment model. Echocardiography was performed within 24 h of admission and at 3 months to record the ejection fraction (EF), the wall motion score index (WMSI), the ratio of the mitralinflow velocity to the early diastolic velocity (E/E0)and the myocardial performance index (MPI). The mean global WR of the BMIPP was 22.12 +/- 7.22%, and it was significantly correlated with the improvement of the WMSI (r = 0.61, P\0.004). However,the relative changes of the EF, E/E0 and MPI were not correlated with the WR. The BMIPP defect score (18 +/- 10) was significantly correlated with the WMSI on admission (r = 0.74, P = 0.0002), but the defect score was not correlated with the relative changes of any of the echocardiographic parameters. We proved that the WR of the BMIPP is a promising indicator of improvement of the LV wall motion (WMSI) following ST-segment elevation myocardial infarction and successful reperfusion.

Prognostic value of myocardial metabolic imaging with BMIPP in the spectrum of coronary artery disease: a systematic review.

BACKGROUND: We conducted a systematic review to summarize the current literature on the prognostic value of BMIPP imaging, fatty-acid metabolic imaging, for the prediction of cardiovascular events in coronary artery disease. METHODS AND RESULTS: Electronic databases (including Japanese medical literature search engines) were searched by a Japanese investigator using a predefined search strategy. Eleven studies, all conducted in Japan, were included in the meta-analysis. In three studies involving 541 patients with suspected acute coronary syndrome who were excluded for acute myocardial infarction (AMI), an abnormal finding on BMIPP imaging was significantly associated with future hard events (cardiac death or non-fatal myocardial infarction). The negative predictive value of BMIPP imaging for future hard events was 98.9% (96.8-99.7%) over 3.5 years. In six studies involving 542 patients with AMI, a larger defect on BMIPP imaging was significantly associated with future hard events. The prognostic value of perfusion-metabolism mismatch compared with myocardial perfusion imaging was dependent upon the relative timing of BMIPP imaging, revascularization, and myocardial perfusion damage. CONCLUSIONS: BMIPP imaging is useful for the risk stratification of patients with coronary artery disease, particularly patients with acute chest pain.

Fatty acid metabolism and myocardial perfusion imaging for the evaluation of global left ventricular dysfunction following acute myocardial infarction: comparisons with echocardiography.

BACKGROUND: Myocardial fatty acid metabolic imaging with beta-methyl iodophenyl pentadecanoic acid (BMIPP) and perfusion imaging with tetrofosmin (TF) combined can predict post ischemic salvageable myocardium and persistent left ventricular (LV) dysfunction. This study was designed for the first time to assess systolic, diastolic and global LV dysfunction considering BMIPP and TF mismatched defect score (MMDS), and comparing this approach with the conventional Doppler echocardiography. METHODS: Thirty four patients with first acute myocardial infarction (AMI) were enrolled, and all of them underwent percutaneous coronary intervention (PCI). BMIPP and Tetrofosmin (TF) scans were performed at 7+/-3.5 days of admission. Echocardiography was performed within 24 h of admission, at an interval of 1 and 3 months. MMDS was compared with systolic: ejection fraction (EF), wall motion score index (WMSI), fractional shortening (FS); diastolic: mitral valve deceleration time (MVDT), E/E', left atrial volume index (LAVI); combined systolic and diastolic parameter: left ventricular myocardial performance index (LVMPI). RESULTS: A good correlation was observed between BMIPP and TF defect score (p<0.00001), and in 31 (91%) patients BMIPP defect score was higher than that of TF. The MMDS showed significant correlation with EF (r=-0.64, p=<0.00001), WMSI (r=0.61, p<0.0001), and FS(r=-0.65, p<0.00001), LAVI (r=-0.32, p<0.05), and LVMPI (r=0.37, p<0.02) during follow up echocardiography at 1 month. MVDT and E/E' did not correlate with MMDS. CONCLUSION: Perfusion-metabolism mismatched defect score was well correlated with the evolution of global left ventricular dysfunction following AMI evidenced from conventional Doppler echocardiography.

Targeting murine heart and brain: visualisation conditions for multi-pinhole SPECT with (99m)Tc- and (123)I-labelled probes.

PURPOSE: The study serves to optimise conditions for multi-pinhole SPECT small animal imaging of (123)I- and (99m)Tc-labelled radiopharmaceuticals with different distributions in murine heart and brain and to investigate detection and dose range thresholds for verification of differences in tracer uptake. METHODS: A Triad 88/Trionix system with three 6-pinhole collimators was used for investigation of dose requirements for imaging of the dopamine D(2) receptor ligand [(123)I]IBZM and the cerebral perfusion tracer [(99m)Tc]HMPAO (1.2-0.4 MBq/g body weight) in healthy mice. The fatty acid [(123)I]IPPA (0.94 +/- 0.05 MBq/g body weight) and the perfusion tracer [(99m)Tc]sestamibi (3.8 +/- 0.45 MBq/g body weight) were applied to cardiomyopathic mice overexpressing the prostaglandin EP(3) receptor. RESULTS: In vivo imaging and in vitro data revealed 45 kBq total cerebral uptake and 201 kBq cardiac uptake as thresholds for visualisation of striatal [(123)I]IBZM and of cardiac [(99m)Tc]sestamibi using 100 and 150 s acquisition time, respectively. Alterations of maximal cerebral uptake of [(123)I]IBZM by >20% (116 kBq) were verified with the prerequisite of 50% striatal of total uptake. The labelling with [(99m)Tc]sestamibi revealed a 30% lower uptake in cardiomyopathic hearts compared to wild types. [(123)I]IPPA uptake could be visualised at activity doses of 0.8 MBq/g body weight. CONCLUSION: Multi-pinhole SPECT enables detection of alterations of the cerebral uptake of (123)I- and (99m)Tc-labelled tracers in an appropriate dose range in murine models targeting physiological processes in brain and heart. The thresholds of detection for differences in the tracer uptake determined under the conditions of our experiments well reflect distinctions in molar activity and uptake characteristics of the tracers.

Synthesis and bio-evaluation of a new fatty acid derivative for myocardial imaging.

Development of a (99m)Tc-fatty acid analogue is of interest, as (99m)Tc is logistically advantageous over the cyclotron-produced (11)C and (123)I. Synthesis of a 16 carbon fatty acid derivative and its radiolabeling with the novel [(99m)TcN(PNP)](2+) core is described here. Hexadecanedioic acid was conjugated to cysteine in an overall yield of 55%. This ligand could be labeled with (99m)Tc via the [(99m)TcN(PNP)](2+) core, in 80% yield, as a mixture of two isomers (syn and anti). The major isomer isolated by HPLC was used for bioevaluation studies in swiss mice and compared with radioiodinated iodophenyl pentadecanoic acid (IPPA), an established agent for myocardial metabolic imaging. (99m)Tc-labeled complex cleared faster from the non-target organs, namely, liver, lungs, and blood compared to that of [(125)I]-IPPA. However, the complex exhibited lower uptake and faster washout from the myocardium as compared to [(125)I]-IPPA.