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PubMed2000

Non-invasive radiotracer imaging as a tool for drug development.

Non-Invasive Radiotracer Imaging (NIRI) uses either short-lived positron-emitting isotopes, such as 11C and 18F, for Positron Emis ion Tomography (PET) or single photon emitting nuclides, e.g., 123I, which provide images using planar imaging or Single-Photon Emission Computed Tomography (SPECT). These high-resolution imaging modalities provide anatomical distribution and localization of radiolabeled drugs, which can be used to generate real time receptor occupancy and off-rate studies in humans. This can be accomplished by either isotopically labeling a potential new drug (usually with 11C), or indirectly by studying how the unlabelled drug inhibits specific radioligand binding in vivo. Competitive blockade studies can be accomplished using a radiolabeled analogue which binds to the site of interest, rather than a radiolabeled version of the potential drug. Imaging, particularly PET imaging, can be used to demonstrate the effect of a drug through a biochemical marker of processes such as glucose metabolism or blood flow. NIRI as a development tool in the pharmaceutical industry is gaining increased acceptance as its unique ability to provide such critical information in human subjects is recognized. This section will review recent examples that illustrate the utility of NIRI, principally PET, in drug development, and the potential of imaging advances in the development of cancer drugs and gene therapy. Finally, we provide a brief overview of the design of new radiotracers for novel targets.

Animals↗
PubMed1986

Uptake of meta-iodobenzylguanidine by bovine chromaffin granule membranes.

meta-Iodobenzylguanidine, an adrenal imaging agent used for the scintigraphic detection of human pheochromocytoma, is a substrate for the monoamine uptake system of chromaffin granules. It is accumulated by bovine chromaffin granule membrane vesicles in the presence of ATP, and it can be released by an osmotic shock. The uptake is dependent upon the generation of an H+-electrochemical gradient by an ATP-dependent H+ pump since it is blocked by an H+ ionophore and since meta-iodobenzylguanidine uptake can be driven by imposing an artificial pH gradient (inside acidic) on the membrane vesicles. The transport is saturable and its Km value (2.0 microM at pH 8.0) is similar to that of noradrenaline (5.3 microM). Transport occurs through the monoamine transporter since it is blocked by the same inhibitors, tetrabenazine and reserpine, and also by the transporter substrates noradrenaline and serotonin. Noradrenaline inhibits meta-iodobenzylguanidine uptake competitively (Ki = 13 microM). In addition, meta-iodobenzylguanidine displaces dihydrotetrabenazine and reserpine from their binding sites on chromaffin granule membranes. It is thus likely that, after in vivo administration, [131I] meta-iodobenzylguanidine is ultimately stored in chromaffin granules and that it is translocated by the monoamine transporter.

3-Iodobenzylguanidine↗
PubMed1995

Effects of smoking on bronchial clearance of technetium-99m-DTPA and indium-113m-DTPA.

UNLABELLED: In asymptomatic smokers, epithelial permeability in the distal lung regions is increased. To date, the effect of smoking on the epithelial permeability in proximal lung regions is still debated. The measurement of bronchial clearance of inhaled radiolabeled diethylene-triaminepentaacetic acid (BC-DTPA) can be used to assess epithelial permeability of proximal bronchi, but there are two potential limitations to this method: in vivo breakdown of 99mTc-DTPA in smokers and mucociliary transport of DTPA. METHODS: Eight nonsmokers and eight asymptomatic smokers were studied. We used a spinning disk system to generate an aerosol of large particles of 99mTc-DTPA or 113mIn-DTPA (MMAD 6.3 microns). To measure the bronchial clearance of 99mTc-DTPA and 113mIn-DTPA, we analyzed the perihilar regions of the lung. To determine the contribution of mucociliary transport, we measured the activity over a tracheal region of interest (ROI) in eight nonsmokers. RESULTS: Technetium-99m-DTPA bronchial clearance did not differ in smokers (1.16 +/- 0.54%/min; mean +/- s.d.) or nonsmokers (1.29 +/- 0.51%/min; ns). The 113mIn-DTPA bronchial clearances in nonsmokers (1.24 +/- 0.51%/min) and in smokers (1.01 +/- 0.66%/min) were similar to the 99mTc-DTPA bronchial clearances (ns). In the tracheal ROI, we found no increase in activity. CONCLUSION: In smokers, BC-DTPA was not increased compared to nonsmokers. In contrast to distal lung regions, there was no evidence of breakdown of the 99mTc-DTPA complex in the proximal regions of smokers' lungs. Mucociliary clearance does not significantly contribute to BC-DTPA.

Adult↗
PubMed1981

Metabolic myocardial imaging with 123I-labeled heptadecanoic acid in patients with angina pectoris.

The potential value of 123I-heptadecanoic acid (123I-H degree A) in myocardial scintigraphy has recently been assessed in patients with acute myocardial infarction (AMI) by studying regional myocardial metabolism (Van der Wall et al. 1981 a). To determine the metabolic behavior of 123I-H degree A in patients with stable angina pectoris (AP) as well, 30 patients with AP were included in this study: 18 patients were exercised and 12 patients were studied at rest. Regional myocardial metabolism was evaluated by generating background subtracted time-activity curves, acquired by external detection over normally perfused and ischemic regions during a 30-min period after intravenous injection of 123I-H degree A. Following monoexponential curve-fitting, clearance rates were measured representing turnover rate (T1/2) of 123I-H degree A. The exercise group showed prolonged T1/2 values of 46.7 +/- 7.1 min (mean +/- SD) in ischemic regions and 28.7 +/- 3.6 min in normally perfused regions. The group at rest did not reveal any scintigraphic abnormalities and showed normal T1/2 values in all myocardial regions (29.1 +/- 4.7 min). Our observations of prolonged turnover rates in ischemic areas differ from the results of our recent study in patients with AMI, which demonstrated fast turnover rates in infarcted tissue. These data imply that 123I-H degree A permits the study of myocardial metabolism in patients with AP and the discrimination of normally perfused, reversibly ischemic (AP) and irreversibly ischemic (AMI) myocardium.

Adult↗
PubMed1997

Simulation of the stripe sign in a scintigraphic model of the lungs.

Using a virtual model of the lungs, we investigated the nature of the 'stripe sign' which is sometimes encountered in pulmonary scintigraphy. A model of the segmental anatomy of the lungs was developed from a number of sources and counts generated within the phantom by Monte-Carlo simulation of photon emission. Multiple segmental and subsegmental defects were created in both lungs and submitted for blinded reporting of the 'stripe sign'. Images were resubmitted for reporting with the contralateral lung removed. The stripe sign was reported in 32 of the 117 studies performed. Nearly half of these were present in defects involving approximately 25% of a segment and the sign was most commonly seen in the lateral projection. Removal of activity from the contralateral lung abolished the sign in only 2 of 32 cases. We conclude that shine through of activity from the contralateral lung is a mechanism rarely responsible for the stripe sign. Most occurrences of the sign are due to interposition of activity from unaffected areas of the same lung between the defect and the periphery of the lung. Orientation of the segments, particularly in the lung bases, accounts for the lateral projection being the most common view in which the sign is present.

Humans↗
PubMed1983

Computed tomography, ultrasound, and scintigraphy of the liver in patients with colon or breast carcinoma: a prospective comparison.

A prospective evaluation of computed tomography (CT), ultrasonography (US), and Tc-99m sulfur colloid scintigraphy of the liver was performed in 189 patients who had either colon (n = 129) or breast (n = 60) carcinoma. Imaging was performed with fourth-generation CT scanners, gray-scale or phased array ultrasound scanners, and 37-tube gamma cameras. Studies were evaluated independently and receiver operating characteristic (ROC) curves were constructed. In addition, a standard 2 X 2 matrix analysis was performed. In patients who had all three examinations (n = 122), the matrix analysis showed that CT had a slightly higher sensitivity (0.93) than scintigraphy (0.86) or US (0.82); specificities were 0.88, 0.83, and 0.85, respectively. These differences were not statistically significant. However, ROC curves showed that CT had the highest true-positive ratio at every false-positive ratio, and that US had the lowest. The performance of CT did not differ significantly from that of scintigraphy, but was better than that of US (p less than .05), especially in patients with breast carcinoma. Overall, CT provided the most accurate means for detecting liver metastases from both primary lesions.

Breast Neoplasms↗
PubMed2002

The effects of thyrotoxicosis and its treatment on central arterial stiffness.

OBJECTIVE: To assess central arterial stiffness in thyrotoxicosis using the technique of pulse wave analysis. DESIGN: Case control study designed to determine the effect of thyrotoxicosis on central arterial stiffness and at 6 months after radioiodine treatment. PATIENTS: Twenty (18 women and 2 men) thyrotoxic patients and 20 age- and sex-matched controls were studied at baseline. Thyrotoxic patients were re-studied at 6 months following treatment of thyrotoxicosis with 555 MBq (131)I with no additional therapy for the six-month period. MEASUREMENTS: Using the sphygmocor apparatus, peripheral pressure waveforms were recorded non-invasively from the radial artery and central pressure waveforms were generated from these. Indices of arterial stiffness, central augmentation index (AI), augmentation of central arterial pressure (AG) and central blood pressures were derived. AI corrected for heart rate (AIc) was calculated. RESULTS: Thyrotoxic patients recorded a significantly lower AI (means+/-s.e.m.) compared with controls (15.0+/-2.1 vs 28.0+/-2.1%; P<0.0005) even when corrected for differences in heart rate AIc (20.0+/-2.1 vs 28.0+/-2.1%; P<0.005) as well as AG (6.0+/-0.8 vs 10.0+/-1.1 mmHg; P<0.002) but higher pulse pressure (58.0+/-3.5 vs 47.0+/-2.0 mmHg; P<0.02). At 6 months following treatment, a significant rise in AIc (27.0+/-1.8 vs 20.0+/-2.1%; P<0.005) and AG (11.0+/-1.0 vs 6.0+/-0.8 mmHg; P<0.005) was noted. Lipid profiles were comparable between the groups. CONCLUSIONS: These data suggested that subjects with untreated thyrotoxicosis have a decreased augmentation of central arterial pressure or lowered central arterial stiffness that would not appear to contribute to any excess cardiovascular risk in that condition.

Blood Pressure↗
PubMed2005

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers.

PURPOSE: This study reports on the whole-body biodistribution and radiation dosimetry of [11C]raclopride, a dopamine D2 receptor antagonist. METHODS: In three healthy male volunteers, whole-body scans were performed up to 2 h following i.v. injection of 320+/-65 MBq [11C]raclopride. Transmission scans (3 min per step, eight or nine steps according to the height of the subject) in 2D mode were used for subsequent attenuation correction of emission scans. Emission scans (1 min per step, eight or nine steps) were acquired over 2 h. Venous blood samples and urine were collected up to 2 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, intestine, lungs, kidneys and liver was fitted to a mono-exponential model, as an uptake phase followed by a mono-exponential washout, for urinary bladder to generate time-activity curves. Using the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses. RESULTS: Blood pressure and ECG findings remained unchanged after tracer injection. The analysed blood and urine pharmacological parameters did not change significantly after [(11)C]raclopride injection. The primary routes of clearance were renal and intestinal. Ten minutes after injection, high activities were observed in the gall-bladder, kidneys and liver. High activity was observed in the gall-bladder during the whole study. The kidneys, urinary bladder wall, liver and gall-bladder received the highest absorbed doses. The average effective dose of [11C]raclopride was estimated to be 6.7+/-0.4 microSv/MBq. CONCLUSION: The amount of [11C]raclopride required for adequate dopamine D2 receptor imaging results in an acceptable effective dose equivalent, permitting two or three repeated clinical PET imaging studies, with the injection of 222 MBq for each study.

Adult↗
PubMed2006

Non-invasive imaging of neuropathology in a rat model of alpha-synuclein overexpression.

Parkinson's disease is a neurodegenerative disorder affecting the dopaminergic neurons in the substantia nigra. Aggregation of alpha-synuclein appears to play a central role in the pathogenesis. Novel animal models for neurodegeneration have been generated by lentiviral vector-mediated locoregional overexpression of disease-associated genes in the adult brain. We have used lentiviral vectors to overexpress a clinical mutant of alpha-synuclein, A30P, in the rat substantia nigra. This overexpression induced time-dependent cytoplasmic and neuritic accumulation of alpha-synuclein and neurodegeneration. A subgroup of the rats developed asymmetric rotational behavior after administration of amphetamine. In addition, these animals displayed reduced dopamine transporter binding visualized by 123I-FP-CIT microSPECT imaging. The behavioral and microSPECT data were validated by histological analysis. There was a strong correlation between the reduction of dopaminergic neurons in the substantia nigra and the reduction of dopamine transporter binding in the striatum. MicroSPECT imaging enables non-invasive imaging of the neurodegeneration allowing longitudinal follow-up in this new animal model for Parkinson's disease and the evaluation of neuroprotective drugs.

Animals↗
PubMed1991

Recombinant human nerve growth factor is biologically active and labels novel high-affinity binding sites in rat brain.

Iodinated recombinant human nerve growth factor (125I-rhNGF) stimulated neurite formation in PC12 cell cultures with a half-maximal potency of 35-49 pg/ml, compared with 39-52 pg/ml for rhNGF. In quantitative ligand autoradiography, the in vitro equilibrium binding of 125I-rhNGF to brain sections showed a 10-fold regional variation in density and was saturable, reversible, and specifically displaced by up to 74% with rhNGF or murine NGF (muNGF). At equilibrium, 125I-rhNGF bound to these sites with high affinity (Kd 52-85 pM) and low capacity (Bmax less than or equal to 13.2 fmol/mg of protein). Calculation of 125I-rhNGF binding affinity by kinetic methods gave average Kd values of 24 and 31 pM. Computer-generated maps revealed binding in brain regions not identified previously with 125I-muNGF, including hippocampus; dentate gyrus; amygdala; paraventricular thalamus; frontal, parietal, occipital, and cingulate cortices; nucleus accumbens; olfactory tubercle; subiculum; pineal gland; and medial geniculate nucleus. NGF binding sites were distributed in a 2-fold increasing medial-lateral gradient in the caudate-putamen and a 2-fold lateral-medial gradient in the nucleus accumbens. 125I-rhNGF binding sites were also found in most areas labeled by 125I-muNGF, including the interpedunucular nucleus, cerebellum, forebrain cholinergic nuclei, caudoventral caudate-putamen, and trigeminal nerve nucleus. 125I-rhNGF binding sites were absent from areas replete with low-affinity NGF binding sites, including circumventricular organs, myelinated fiber bundles, and choroid plexus. The present analysis provides an anatomical differentiation of high-affinity 125I-rhNGF binding sites and greatly expands the number of brain structures that may respond to endogenous NGF or exogenously administered rhNGF.

Animals↗
PubMed1987

Effect of nebulised aerosol size on lung deposition in patients with mild asthma.

A radioaerosol technique has been used to investigate whether the size distribution of aerosols released from a jet nebuliser affects the amount of aerosol delivered to the lungs. Six subjects with mild asthma (FEV1 81% of predicted) were studied on three occasions. On each visit they received one of three aerosols tagged with technetium-99m in 0.9% saline. The aerosols were generated by either (A) a Turret nebuliser operated at 8 l min-1 (mass median diameter (MMD) 1.8 micron); (B) an Upmist nebuliser operated at 6 l min-1 (MMD 4.6 microns); or (C) an Inspiron Mini-neb operated at 4 l min-1 (MMD 10.3 microns). The aerosols were given in a randomised single blind manner and inhaled under identical conditions of inspiratory volume and frequency. The mean (SD) percentage of aerosols A, B, C released from the nebulisers during inhalation that was recovered in an expiratory filter was 23 (6), 25 (4), and 24 (4) respectively. Of the aerosols released from the nebuliser and deposited in the body, the percentage deposited in the lung was 79 (3) for aerosol A, 59 (4) for aerosol B, and 44 (5) for aerosol C. The remaining aerosol was deposited in the oropharynx and swallowed. It is concluded that small nebulised aerosols (MMD less than 2 microns) deliver a larger dose to the lungs and should be used to maximise lung deposition.

Adult↗
PubMed1977

Analysis of left ventricular function from multiple gated acquisition cardiac blood pool imaging. Comparison to contrast angiography.

Global ventricular function was evaluated by both multiple gated cardiac blood pool scans (MUGA) and contrast ventriculograms in a group of 17 patients with suspected coronary artery disease. The contrast ventriculograms were analyzed frame by frame to generate a volume versus time curve for each patient, while the tracer data were analyzed by two methods: 1) the standard method, in which the left ventricle is identified on the end-diastolic frame and the background corrected activity under the region of interest obtained from the entire cardiac cycle, and displayed as a time versus activity curve; and 2) by a semi-automatic method in which the computer applies a threshold detection program to define the ventricular borders, and activity in the chamber at each point in the cardiac cycle is defined after background correction. The tracer data in each patient were analyzed independently by four observers. The tracer data correlated with the contrast data on a point by point basis r = 0.87 for the standard method, and 0.93 for the semi-automatic technique. An F test of variance revealed the semi-automatic method superior to the standard approach (P less than 0.05).

Computers↗
PubMedDate not supplied

Effects of altered left ventricular geometry on quantitative technetium 99m sestamibi defect size in humans: perfusion imaging during coronary angioplasty.

BACKGROUND: Serial myocardial perfusion imaging is used to assess exercise-induced myocardial ischemia and myocardial risk area, salvage, and viability in patients with myocardial infarction. In an experimental animal model it has been shown that abnormal regional wall motion and altered left ventricular geometry can produce apparent perfusion defects independent of changes in blood flow. The effects of regional alteration in ventricular geometry on perfusion images in humans are not defined. The purpose of our investigation was to evaluate quantitatively the effect of altered left ventricular geometry on myocardial perfusion imaging with technetium 99m sestamibi during coronary angioplasty. METHODS AND RESULTS: Nine patients with normal baseline left ventricular function referred for angioplasty of the left anterior descending coronary artery were studied. 99mTc sestamibi was administered intravenously before angioplasty. Baseline planar electrocardiographic-gated imaging was performed. Imaging was repeated in the catheterization laboratory during angioplasty vessel occlusion when altered left ventricular geometry was produced and again later after angioplasty. Summed static, end-systolic, and end-diastolic images were generated from the electrocardiographic-gated acquisitions. Circumferential count profiles of images obtained during percutaneous transluminal coronary angioplasty (PTCA) were compared with those of a normal 99mTc sestamibi database and their own baseline images. Defect integral (the area below the reference profile) and nadir (maximum percent decrease in activity) were derived. Compared with a normal database, new quantitative defects appeared on PTCA-summed images in only two patients. The defects were small to moderate in size. However, compared with their own baseline profile, six patients had quantitative defects during PTCA (mean defect integral 3 +/- 2; mean defect nadir 12% +/- 7%). Defect nadir was larger on end-diastolic images compared with summed images (22% +/- 7% and 12% +/- 7%, respectively; p < 0.05). CONCLUSIONS: Altered left ventricular geometry may create apparent, albeit small, planar myocardial perfusion defects in humans. Changes in defect size on serial images may be only partially caused by changes in regional wall motion or geometry.

Adult↗
PubMed1994

Recurrent thyroid cancer. Role of surgery versus radioactive iodine (I131)

OBJECTIVE: This retrospective study compared treatment and survival of patients with recurrent well-differentiated thyroid cancer that was diagnosed exclusively by I131 scanning, or by clinical examination. SUMMARY BACKGROUND DATA: Despite the usual excellent prognosis of differentiated thyroid cancer, approximately half of patients who developed a recurrence eventually succumb to the disease. It has been speculated, but not proven, that recurrent disease detected solely by I131 scanning may offer a better prognosis than recurrences detected clinically and be amendable to I131 ablative therapy without the addition of surgical resection. METHODS: Seventy-four cases of recurrent differentiated thyroid cancer were identified retrospectively and examined regarding the location of recurrence, mode of detection of recurrent disease, treatment of recurrence, and outcome of patients. Using Fischer exact testing, outcome results for recurrences detected exclusively by I131 scan was compared to that of clinically diagnosed recurrences; among clinically detected recurrent cases, treatment with surgery only was compared to surgery/I131 ablation. Kaplan-Meier actuarial survival curves were generated for clinically detected recurrent cancer treated by surgery only and compared to those treated by surgery and I131 ablation using Gehan-Wilcoxon and log-rank analysis. RESULTS: Recurrences located most commonly were regional (53%), followed by local (28%), distant metastasis (13%), and combined locoregional (6%). Among patients whose recurrence was detected scintigraphically, only 9.5% had persistence of disease or were dead of disease compared to 54.0% of patients with clinically detected recurrences. Radioactive iodine ablation in scintigraphically detected recurrences salvaged 18 of 20 patients (90%). Among clinically detected recurrences, surgery alone salvaged 12 of 21 patients (57%), whereas the addition of I131 ablation to surgery salvaged only 3 of 15 patients (20% p = 0.05). CONCLUSION: The probability of dying or living with persistent disease after treatment of recurrent thyroid cancer is less for I131 detected recurrences compared to clinically diagnosed recurrences; I131 ablation without surgery constitutes adequate therapy for scintigraphically detected recurrences. In clinically recurrent disease, the addition of I131 ablation to curative resection does not appear to improve survival.

Actuarial Analysis↗
PubMed2006

Identification of simulated microcalcifications in white noise and mammographic backgrounds.

This work investigates human performance in discriminating between differently shaped simulated microcalcifications embedded in white noise or mammographic backgrounds. Human performance was determined through two alternative forced-choice (2-AFC) experiments. The signals used were computer-generated simple shapes that were designed such that they had equal signal energy. This assured equal detectability. For experiments involving mammographic backgrounds, signals were blurred to account for the imaging system modulation transfer function (MTF). White noise backgrounds were computer generated; anatomic background patches were extracted from normal mammograms. We compared human performance levels as a function of signal energy in the expected difference template. In the discrimination task, the expected difference template is the difference between the two signals shown. In white noise backgrounds, human performance in the discrimination task was degraded compared to the detection task. In mammographic backgrounds, human performance in the discrimination task exceeded that of the detection task. This indicates that human observers do not follow the optimum decision strategy of correlating the expected signal template with the image. Human observer performance was qualitatively reproduced by non-prewhitening with eye filter (NPWE) model observer calculations, in which spatial uncertainty was explicitly included by shifting the locations of the expected difference templates. The results indicate that human strategy in the discrimination task may be to match individual signal templates with the image individually, rather than to perform template matching between the expected difference template and the image.

Artifacts↗
PubMedDate not supplied

Synthesis, characterization, and labeling with 99mTc/188Re of peptide conjugates containing a dithia-bisphosphine chelating agent.

Radiolabeling of small receptor-avid peptides at specific predetermined chelation sites with radioactive metals has been an effective approach for production of target-specific radiopharmaceuticals for diagnosis and therapy of diseases. Among various electron-donating groups found on chelator frameworks, phosphines are unique because they display versatile coordination chemistry with a wide range of transition metals. We have recently reported the utility of a dithia-bis(hydroxymethyl)phosphine-based (P2S2) bifunctional chelating agent (BFCA) containing air-stable primary phosphine groups to form 99mTc-labeled receptor-avid peptides by the preconjugation approach. Here we report a novel strategy for labeling small peptides with both 99mTc and 188Re using the P2S2-COOH (6,8-bis[3-(bis(hydroxymethyl)phosphanyl)propylsulfanyl]octanoic acid) BFCA by a postconjugation radiolabeling approach. The first step in this approach involves the coupling of the corresponding (PH2)2S2-COOH intermediate to the N-terminus of the peptide(s). Formylation of P-H bonds with aqueous formaldehyde in the presence of HCl in ethanol affords the corresponding (hydroxymethyl)phosphine-P2S2-peptide conjugates in the form of an oxidatively stable phosphonium salt. The P2S2-peptide conjugates are generated (where the PH2 groups are converted to P(CH2OH)2 groups) by treatment of the P2S2-peptide phosphonium salt(s) with 1 M sodium bicarbonate solution at pH 8.5. Complexation of BFCA conjugates with 99mTc is achieved by direct reduction with Sn(II) tartarate to yield the 99mTc-P2S2-peptide conjugate in near quantitative yields. Complexation of the BFCA conjugates with 188Re is achieved by transchelation with 188Re citrate in yields of >/=90%. In this study, (PH2)2S2-COOH BFCA was conjugated to model peptides. The glycineglycine ethyl ester (GlyGlyOEt)-(PH2)2S2-COOH BFCA conjugate was converted to the hydroxymethylene phosphine form and complexed with 99mTc to produce the 99mTcO2-P2S2-GlyGlyOEt conjugate 8 in RCPs of >/=95%. This singular 99mTc product is stable over 24 h in aqueous solution as confirmed by HPLC. Identical retention times of the 99mTcO2-P2S2-GlyGlyOEt complex and its cold rhenium analogue (ReO2-P2S2-GlyGlyOEt) on HPLC indicates similarity in structures at the macroscopic and the tracer levels. The utility of this postconjugation strategy was further demonstrated by synthesizing a P2S2-D-Lys6-LHRH conjugate and producing its corresponding 99mTc complex in RCPs of >/=88%. Finally, the P2S2-5-Ava-BBN[7-14]NH2 bombesin (BBN) analogue was synthesized, the PH2 groups converted to P(CH2OH)2 groups and subsequently labeled with 188Re to yield a 188Re-labeled bombesin analogue with a RCP of >/=90%. The biological integrity of this conjugate was demonstrated in both in vitro and in vivo. The results of this investigation demonstrate that the (PH2)2S2-COOH BFCA can be conveniently used as a precursor for labeling small receptor-avid peptides with diagnostic (99mTc) and therapeutic (188Re) radionuclides via the postconjugation approach in high yields.

3T3 Cells↗
PubMed2006

Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides.

UNLABELLED: Recent studies have shown that indirect effects of ionizing radiation may contribute significantly to the effectiveness of radiotherapy by sterilizing malignant cells that are not directly hit by the radiation. However, there have been few investigations of the importance of indirect effects in targeted radionuclide treatment. Our purpose was to compare the induction of bystander effects by external beam gamma-radiation with those resultant from exposure to 3 radiohaloanalogs of metaiodobenzylguanidine (MIBG): (131)I-MIBG (low-linear-energy-transfer [LET] beta-emitter), (123)I-MIBG (potentially high-LET Auger electron emitter), and meta-(211)At-astatobenzylguanidine ((211)At-MABG) (high-LET alpha-emitter). METHODS: Two human tumor cell lines-UVW (glioma) and EJ138 (transitional cell carcinoma of bladder)-were transfected with the noradrenaline transporter (NAT) gene to enable active uptake of MIBG. Medium from cells that accumulated the radiopharmaceuticals or were treated with external beam radiation was transferred to cells that had not been exposed to radioactivity, and clonogenic survival was determined in donor and recipient cultures. RESULTS: Over the dose range 0-9 Gy of external beam radiation of donor cells, 2 Gy caused 30%-40% clonogenic cell kill in recipient cultures. This potency was maintained but not increased by higher dosage. In contrast, no corresponding saturation of bystander cell kill was observed after treatment with a range of activity concentrations of (131)I-MIBG, which resulted in up to 97% death of donor cells. Cellular uptake of (123)I-MIBG and (211)At-MABG induced increasing recipient cell kill up to levels that resulted in direct kill of 35%-70% of clonogens. Thereafter, the administration of higher activity concentrations of these high-LET emitters was inversely related to the kill of recipient cells. Over the range of activity concentrations examined, neither direct nor indirect kill was observed in cultures of cells not expressing the NAT and, thus, incapable of active uptake of MIBG. CONCLUSION: Potent toxins are generated specifically by cells that concentrate radiohalogenated MIBG. These may be LET dependent and distinct from those elicited by conventional radiotherapy.

Bystander Effect↗
PubMed2004

18F-FDG PET for detecting recurrent head and neck cancer, local lymph node involvement and distant metastases. Comparison of qualitative visual and semiquantitative analysis.

AIM: Assessment of the clinical value of (18)F-FDG-PET for detection of recurrent head and neck cancer, local lymph node involvement and distant metastases comparing a qualitative visual with a semiquantitative analysis (SUV values). PATIENTS, METHODS: Retrospective evaluation of 73 (18)F-FDG PET studies in 55 patients by use of a four-step qualitative visual grading system and calculation of standard uptake values in pathological lesions. Calculation of SUV values in normal regions for generating a map of physiological (18)F-FDG distribution. Correlation to histopathological findings and clinical follow-up. RESULTS: 1. Qualitative visual analysis of (18)F-FDG PET studies: a) local recurrence sensitivity 79%, specificity 97%, positive predictive value 95%, negative predictive value 85%, and diagnostic accuracy 89%; b) local metastatic lymph nodes 100%, 95%, 85%, 100%, 96%; c) distant metastases 100%, 98%, 86%, 100%, 98%, respectively. 2. Semiquantitative analysis had only little incremental, non-significant value in comparison to qualitative visual analysis for the detection of a local recurrence in two patients: a) local recurrence: sensitivity 83%, specificity 100%, positive predictive value 100%, negative predictive value 88%, and diagnostic accuracy 93%; b) local metastatic lymph nodes or c) distant metastases did not change in comparison to qualitative visual analysis. CONCLUSION: (18)F-FDG PET is an effective tool for re-staging of patients with suspected recurrence after therapy for head and neck cancer.

Carcinoma, Squamous Cell↗