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The novel compound, (S)-amino-2-methyl-4-[(76)Br]bromo-3-(E)-butenoic acid (BrVAIB, [(76)Br]5), was characterized against the known system A tracer, IVAIB ([(123)I]8). [(76)Br]5 was prepared in a 51% ± 19% radiochemical yield with high radiochemical purity (≥98%). The biological properties of [(76)Br]5 were compared with those of [(123)I]8. Results showed that [(76)Br]5 undergoes mixed amino acid transport by system A and system L transport, while [(123)I]8 had less uptake by system L. [(76)Br]5 demonstrated higher uptake than [(123)I]8 in DBT tumors 1 h after injection (3.7 ± 0.4% ID/g vs 1.5 ± 0.3% ID/g) and also showed higher uptake vs [(123)I]8 in normal brain. Small animal PET studies with [(76)Br]5 demonstrated good tumor visualization of intracranial DBTs up to 24 h with clearance from normal tissues. These results indicate that [(76)Br]5 is a promising PET tracer for brain tumor imaging and lead compound for a mixed system A and system L transport substrate.

We investigated the characteristics of the regional rat brain distribution of radio-brominated o-bromo-decalinvesamicol (OBDV) in vivo to evaluate its potential as a PET ligand for vesicular acetylcholine transporter (VAChT). In in vivo biodistribution study, the specific brain regional accumulation of [(77) Br]OBDV was revealed 30 min after intravenous injection. The specific brain regional accumulation of [(77) Br]OBDV was significantly inhibited by co-injection of (+/-)-vesamicol. In contrast, no significant inhibition of the uptake of [(77) Br]OBDV in all brain regions was observed with co-injection of (+)-pentazocine (selective σ-1 receptor agonist) and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine, [(+)-3-PPP] (σ-1 and σ-2 receptor agonist) with [(77) Br]OBDV. [(77) Br]OBDV accumulation in VAChT-rich brain regions was observed in ex vivo autoradiography. These results showed that [(77) Br]OBDV selectively bound to VAChT with high affinity in rat brain in vivo. Hence, OVBDV radiolabelled with more suitable (76) Br was suggested to be a potent VAChT ligand for PET., (© 2014 Wiley Periodicals, Inc.)

Introduction: Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy., Method: 16alpha,17alpha-[(R)-1'-alpha-(5-[(76)Br]Bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione ([(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (3)), a PR ligand with relative binding affinity (RBA)=65 and log P(o/w)=5.09+/-0.84, was synthesized via a two-step reaction, and its tissue biodistribution and metabolic stability were evaluated in estrogen-primed immature female Sprague-Dawley rats., Results: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was synthesized in 5% overall yield with specific activity being 200-1250 Ci/mmol. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 demonstrated high PR-mediated uptake in the target tissue uterus (8.72+/-1.84 %ID/g at 1 h) that was reduced by a blocking dose of unlabeled progestin R5020, but the nonspecific uptake in blood and muscle (2.11+/-0.14 and 0.89+/-0.16 %ID/g at 1 h, respectively) was relatively high. [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 was stable in whole rat blood in vitro, but it was not stable in vivo due to the fast metabolism that occurred in the liver, resulting in the formation of a more polar radioactive metabolite and free [(76)Br]bromide. The level of free [(76)Br]bromide in blood remained high during the experiment (2.11+/-0.14 %ID/g at 1 h and 1.52+/-0.24 %ID/g at 24 h). The tissue distribution of [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 at 1 and 3 h was compared with that of the (18)F analogs, [(18)F]FFNP fluoro furanyl norprogesterone (FFNP) 1 and ketal 2., Conclusion: [(76)Br]16alpha,17alpha-[(R)-1'-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione 3 may have potential for imaging PR-positive breast tumors at early time points, but it is not suitable for imaging at later times or for radiotherapy.

Unlabelled: The aim of this study was to image the extra domain B (ED-B) of fibronectin, an angiogenesis-related target, in solid tumors using small-animal PET. Toward this aim, an ED-B fibronectin-binding human antibody derivative (L19-SIP) was labeled with (76)Br via an enzymatic approach. Biodistribution and imaging studies were performed in human teratoma-bearing mice for up to 48 h after injection., Methods: L19-SIP was labeled with (76)Br using bromoperoxidase/H(2)O(2). The stability of the labeled antibody was tested both in vitro and in vivo. Biodistribution and small-animal imaging studies (PET and CT) were performed in F9-bearing 129/sv mice (n = 3 or 4)., Results: The enzymatic radiobromination approach afforded the labeled antibody in high yield (>55%) under mild reaction conditions. (76)Br-L19-SIP stability in mouse serum proved to be similar to that of the (125)I-labeled analog (>80% of intact material at 48 h after injection). Fast and specific in vivo targeting was obtained in tumors and other organs expressing ED-B fibronectin (i.e., ovaries and uterus). However, slow renal clearance and persistent activity predominately in blood and stomach suggests partial (76)Br-L19-SIP debromination in vivo. This debromination was confirmed in a metabolism study in normal mice. The F9 tumors were clearly imaged by small-animal PET at each considered time point, starting at 5 h up to 48 h after injection., Conclusion: (76)Br-L19-SIP specifically accumulated at the target site, enabling detailed small-animal PET of tumor neovasculature. Therefore, targeting the angiogenesis-associated expression of ED-B fibronectin can be a valuable tool for tumor detection using molecular imaging with PET.

Peroxisome proliferator activated-receptor gamma (PPARgamma) binds to peroxisome receptor response elements with its heterodimeric partner, retinoid X receptor, and regulates downstream gene expression. PPARgamma transcriptionally modulates fat metabolism, and receptor agonists have been developed to treat type II diabetes. PPARgamma is also overexpressed in some tumor cell lines and primary tumors, including breast and prostate tumors. Two PPARgamma antagonists, 2-chloro-5-nitro-N-phenylbenzamide (GW9662) and 2-chloro-5-nitro-N-pyridin-4-yl-benzamide (T0070907), represent good lead compounds for radiotracer development. In the current study, four additional halogen substituted analogs were synthesized and evaluated in a whole cell screening assay for PPARgamma binding activity. Two bromine-containing analogs having EC50 values <5 nM were chosen for bromine-76 radiolabeling. Bromine-76-labeled 2-bromo-5-nitro-N-phenyl-benzamide was selected for subsequent in vitro and in vivo studies due to its superior radiolabeling yield (approximately 70%) and the well-characterized pharmacological properties of its analog GW9662. An in vitro stability study showed that 40% of the compound remained intact in plasma and about 25% in whole blood after 30 min. Biodistribution studies in MDA-MB-435 human breast tumor-bearing nude mice were carried out at 5 min, 30 min, 2 h and 24 h post injection of the radiotracer. Although in vivo metabolite studies demonstrated rapid compound degradation, at least 10% of the parent compound was delivered to the tumor. We are currently exploring second generation analogs of these lead compounds for the development of radiolabeled antagonists of the PPARgamma receptor.

Unlabelled: The sigma(2)-receptor has been shown to be upregulated in proliferating tumors cells. The purpose of this study was to compare 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and 2 new (76)Br-radiolabeled compounds that have a high affinity and selectivity for the sigma(2)-receptor. These are 5-bromo-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide (compound (1)) and 5-bromo-N-(2-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)ethyl)-2-methoxybenzamide (compound (2))., Methods: Two sigma(2)-receptor-binding ligands were prepared, from the corresponding tributylstannyl precursors using standard electrophilic chemistry, (76)Br-compound (1) ((76)Br-1) and (76)Br-compound (2) ((76)Br-2). (18)F-FLT, (76)Br-1, and (76)Br-2 were compared using allograft tumors of the EMT-6 cell line (mouse mammary adenocarcinoma) in biodistribution studies at 5 min, 0.5, 1, and 2 h. Imaging of (76)Br-1 and (18)F-FLT was also performed at 2 and 1 h, respectively., Results: (76)Br-1 and (76)Br-2 were synthesized with yields between 50% and 70% with high specific activity. Both compounds showed uptake into the tumor with tumor-to-normal tissue ratios of (76)Br-1 being greater than both (76)Br-2 and (18)F-FLT. Except for the liver and kidney, all ratios were greater than 1 and uptake into the tumor was shown with microPET imaging for (76)Br-1., Conclusion: We were able to synthesize two (76)Br-radiolabeled compounds with a high yield and specific activity that target the sigma(2) receptor with high affinity and selectivity. The studies presented show that both of the flexible benzamide compounds can identify EMT-6 breast tumors in vivo. (76)Br-1 also has higher tumor-to-normal tissue ratios when compared with (76)Br-2 and (18)F-FLT. The high affinity and low nonspecific binding of (76)Br-1 indicates that it can be a potential PET radiotracer for imaging solid tumors.

Methods have been developed to label oligonucleotides (ODNs) in the 5'-position with (76)Br via a prosthetic group on a hexylamino-linker. The purpose of the study was to explore whether the labelling procedure would prevent specific hybridisation by using reverse transcription-polymerase chain reaction (RT-PCR) followed by sequencing of the PCR product. Antisense ODNs (30 mer, specific for rat Chromogranin A [CgA] mRNA) with phosphodiester (O-ODN) or phosphothioate (S-ODN) backbone, either unlabelled or labelled with (76)Br, served as one of the primers in individual PCR reactions. Using O-ODN as a primer, irrespective of being labelled or not, a selected 225-bp PCR fragment was successfully amplified. However, no amplification was obtained using S-ODN as a primer. The proper PCR products were only detected in the sample prepared from the adrenal gland, but not in that from the heart, liver or kidney. Autoradiographic recording of the gel, after gel electrophoresis, revealed radioactive signals corresponding to the amplified PCR products. The sequence of the PCR product matched the rat CgA mRNA sequence obtained from the EMBL database. RT-PCR is an attractive method to identify the selective binding of modified ODNs to target mRNA. This method confirmed that the labelling with (76)Br did not change the hybridisation ability of antisense O-ODN.

The monoclonal humanized anti-HER2 antibody trastuzumab was radiolabeled with the positron emitter (76)Br (T(1/2) =16.2 h). Indirect labeling was performed using the p-isothiocyanatobenzene derivative of the [(76)Br]undecahydro-bromo-7,8-dicarba-nido-undecaborate(1-) ((76)Br-NBI) as a precursor molecule. (76)Br-NBI was prepared by bromination of the 7-(p-isothiocyanato-phenyl)dodecahydro-7,8-dicarba-nido-undecaborate(1-) ion (NBI) with a yield of 93-95% using Chloramine-T (CAT) as an oxidant. Coupling of radiobrominated NBI to antibody was performed without intermediate purification, in an "one pot" reaction. An overall labeling yield of 55.7 +/- 4.8% (mean +/- maximum error) was achieved when 300 microg of antibody was labeled. The label was stable in vitro in physiological and denaturing conditions. In a cell binding test, trastuzumab remained immunoreactive after labeling.

Paclitaxel (Taxol) is a clinically important chemotherapeutic agent. We describe the synthesis of fluoro-, bromo-, and iodopaclitaxel and their [(18)F]fluoro-, [(76)Br]bromo-, and [(124)I]iodo- analogues. [(18)F]Fluoropaclitaxel shows high uptake and rapid clearance from tissues in rats. Preadministration of paclitaxel in normal rats significantly increases (p < 0.005) retention of [(18)F]fluoropaclitaxel and [(76)Br]bromopaclitaxel in blood (33.0%), heart (32.0%), lung (37.6%) kidney (142.4%); and blood (33.4%), lung (42.3%), kidney (62.4%), respectively. [(18)F]Fluoropaclitaxel uptake in the brain of mdr1a/1b(-/-) mice is increased 1400% (p < 1.3e-07) relative to wild-type controls. Preadministration of paclitaxel or XR9576, a modulator, had little effect on the biodistribution in these mdr1a/1b(-/-) mice. As a result, [(18)F]fluoropaclitaxel will be a useful radiopharmaceutical for the study of multidrug resistant tumors.

The alpha-emitter astatine-211 (T(1/2) = 7.2 h) has great potential for use in targeted radionuclide therapy. Its potent alpha-radiation makes (211)At unsuitable for dose planning. Its x-rays can be used for gamma-camera monitoring of the radioactivity distribution during therapy but not for accurate estimation of absorbed dose in critical organs. This study was intended to establish whether the absorbed dose delivered by astatinated antibody could be accurately determined by analogue labeling with radiohalogens, better suited for quantitative measurements in vivo. PET facilitates quantitative pharmacokinetics; possible halogen labels are, e.g., (76)Br (T(1/2) = 16.2 h) and (124)I (T(1/2) = 4.18 d). Antibody A33 was labeled with (76)Br, (125)I and (211)At using N-succinimidyl-p-halobenzoates. The conjugates were co-injected into Sprague-Dawley rats. Radioactivity concentrations in different organs and tissues were measured at three time points. Pharmacokinetic data were used to calculate absorbed doses. (125)I and (76)Br reflected the biokinetics of astatine reasonably well. The absorbed doses in bladder, kidney, pancreas, liver, bone and brain were determined with 10% accuracy. The absorbed doses in stomach, spleen and thyroid were underestimated by a factor 2-3. Positron-emitting analogues can be used to predict the astatine-derived dose in critical organs. Correction factors should be used for stomach, spleen and thyroid.

The plasma clearance curves of small hydrophilic solutes comprise three exponentials, consistent with a three-compartmental distribution model. A previous comparison between inulin and diethylene triamine penta-acetic acid (DTPA) suggested that these three compartments are in series, the first being plasma and the second and third representing compartments within the extravascular space. Moreover, whilst the total distribution volumes of these two indicators were similar, the volume of the second compartment was higher for DTPA. The purpose of the current study was to investigate whether a solute smaller than DTPA, namely bromide, fits the hypothesis that the second space volume is an inverse function of the size of the solute. Two groups of subjects were studied: group A comprised eight patients undergoing routine diagnostic arteriography and group B, eight patients referred for routine measurement of glomerular filtration rate plus two normal volunteers. (99m)Tc-DTPA and sodium [(77)Br]bromide were intravenously administered simultaneously. In group A, frequent arterial samples were obtained up to 40 min after injection, and antecubital venous samples 30 s after each arterial sample. In group B, frequent venous samples were obtained up to 280 min after injection. Volume measurements based on bromide were corrected for erythrocyte bromide accumulation. In both subject groups, the normalised venous concentration ratio of bromide to DTPA, corrected for red cell bromide uptake, was significantly less than unity in the earliest blood samples, being 0.56 (SD 0.08) at 1 min, consistent with faster diffusion of bromide from plasma to interstitial fluid. Furthermore, the extraction fraction of bromide from plasma to interstitial fluid in the forearm was about 0.6, higher than that of DTPA (about 0.5) in spite of red cell bromide accumulation which equilibrated with plasma bromide within 20 s and resulted in a red cell to plasma concentration ratio of 0.51 (0.09). Nevertheless, the net extraction fractions of the two solutes approached asymptotic values with identical time courses over 20-25 min. The total volume of distribution of bromide in group B was 22.5 (3.8) litres, which was higher than that of DTPA, 18.0 (2.8) litres ( P<0.001). It was assumed that this difference was the result of intracellular bromide accumulation. After correction for this, the combined volume of the first and second spaces was significantly higher for bromide, at 13.9 (2.9) litres, than for DTPA, 12.3 (2.0) litres ( P<0.05), but the volume of the third space, 4.1 (2.8) litres, was less compared with DTPA, for which it was 5.8 (2.2) litres ( P<0.05). The proportion of the total space occupied by the first and second spaces was also higher for bromide, 0.78 (0.14), than for DTPA, for which it was 0.69 (0.09; P<0.05). These data are consistent with a three-in series-compartmental model of solute distribution in which the volume of the second space is an inverse function of solute molecular size while the volume of the third is a positive function of solute size.

Evaluation of oligonucleotides for biomedical applications requires different in vivo and in vitro approaches (pharmacokinetics, biodistribution, macro- and microimaging, metabolism,.), that are performed with different radioisotopes according to the temporal and spatial resolution needed. A method to introduce radioactive isotopes of halogens (fluorine, bromine, and iodine) in a small and stable molecule has been developed. Radiosynthons can then be conjugated with any given oligonucleotide in one step to create the appropriate radiotracer. This general radiolabeling procedure for oligonucleotides is efficient to synthesize (18)F-, (76)Br-, and (125)I-oligonucleotides for biological needs. Applications of the method to biodistribution, metabolism, in vivo and ex vivo imaging of (125)I- and (18)F-labeled oligonucleotides are reported.

Biological half-lives of bromine in 15 different organs and tissues of the rat, in addition to the whole-body half-life, were determined by measuring the radioactive concentration of 82Br-bromide in samples of tissues collected at the time intervals of 12-396 h from animals that continuously (up to 17 d) received 82Br-labeled bromide in their drinking water. The half-life values, calculated from the experimental data by the method of gradual estimates of the parameters in question with the SPSS statistical program, ranged from 94.3+/-14.6 h in the thyroid gland to 235.0+/-88.9 h in liver. In most of the studied tissues, the biological half-lives of bromine were shorter than in the whole body, in which it equaled 197.8+/-22.2 h. Significant correlation between the values of the steady-state concentration of bromide and of the biological half-life was found for most tissues (except for liver). The steady-state concentrations of 82Br in tissues are probably proportional to the magnitude of bromide space, and, consequently, of chloride space.

The distribution of 82Br-bromide in 15 different organs and tissues of rats has been determined by high-resolution gamma-ray spectrometry and by the scintillation counting technique at different times after the application of Na 82Br, either by subcutaneous injection or by continuous administration in the drinking water. The amount of 82Br-bromide in the various tissues reached its largest uptake within a few hours, and the concentration ratio of 82Br in the tissues to blood remained practically constant between 8 and 396 h after the application. The whole stomach of rats was the only organ of those investigated that had a larger uptake of 82Br than blood. Contrary to some previous findings, the concentration of radiobromide in the thyroid was found not to exceed that in the blood. A remarkably high concentration of 82Br was found in the skin, which represented, because of its large mass, the most abundant depot of bromide in the body of rats. The demonstrated excretion of bromide was mainly renal, at a rate of approximately 5% of the administered dose per 24 h.

5-Bromo-2'-deoxyuridine (BrUdR) labeled with 77Br and 76Br was compared with 5-iodo-2'-deoxyuridine (IUdR) labeled with 125I or 131I, first in vitro then in in vivo experiments in mice. The results showed a significantly higher incorporation of BrUdR into DNA than IUdR, which can be explained by the greater similarity (size and surface hydrophilicity of the molecules) of BrUdR to thymidine. Both tracers are dehalogenated quickly in vivo but not in vitro. Free bromide is excreted more slowly than iodide, resulting in a higher background activity level after the application of [76Br]BrUdR and compensates for the favorable DNA incorporation. 76Br has more favorable properties than 124I for imaging purposes with positron emission tomography (PET) because of a very convenient half-life (16 h vs. 4.15 days) and about double the positron yield per decay. However, the more favorable physical properties are balanced by the slower excretion and thus the estimated radiation dose is higher in the case of 76Br than 124I. Thus, both tracers, [124I]IUdR and [76Br]BrUdR are potentially suitable but not optimal to measure cell proliferation in vivo. The difference between the two tracers is small and the extrapolation from mice to human difficult, and thus it cannot be concluded if one of the tracers would be better than the other for imaging of cancer patients.

The development of suitable radioligands for brain imaging of the serotonin transporter is of great importance for the study of depression and other affective disorders. The potent and selective serotonin transporter ligand, 5-iodo-6-nitro-2-piperazinylquinoline, has been labelled with iodine-123 and used as a radioligand for single photon emission computerized tomography. To evaluate the potential of the bromine-76-labelled analogue, 5-bromo-6-nitroquipazine, as a radioligand for positron emission tomography (PET), its brain distribution and binding characteristics were examined in rats. In vivo brain distribution and ex vivo autoradiography demonstrated that [76Br]5-bromo-6-nitroquipazine enters the brain rapidly. The regional brain distribution of [76Br]5-bromo-6-nitroquipazine was consistent with the known distribution of serotonin transporters in the midbrain, pons, thalamus, striatum, and neocortex. Specific binding was inhibited by the selective serotonin reuptake inhibitor citalopram. The peripheral metabolism in plasma was rapid, but more than 90% of the radioactivity in brain represented unchanged radioligand 2 h postinjection (p.i.). A preliminary PET study was also performed in a baboon. Following the intravenous injection of [76Br]5-bromo-6-nitroquipazine in a baboon, there was a conspicuous accumulation of radioactivity in thalamus, striatum, and pons. The radioactivity in these brain regions was 1.5 times higher than in the cerebellum at 3 h and 2.5-4 times higher at 24 h. A rapid metabolism of the radioligand in plasma was observed (38% unchanged after 5 min). The results indicate that [76Br]5-bromo-6-nitroquipazine has potential for PET imaging of the serotonin transporter.

A monoclonal antibody labeled with the positron-emitting radionuclide 76Br (T(1/2) 16.2 h) has previously been shown useful for positron emission tomography (PET) imaging of experimental tumors. Our aim in the present study was to investigate the effects of the complex decay scheme of this radionuclide on normal organ dosimetry and PET image quality. Three mini-pigs were injected intravenously with 46-75 MBq of the 76Br-labeled anti-CEA antibody 38S1, and the whole-body kinetics followed by PET imaging for 19 h. From PET data, absorbed doses in human organs were estimated using the MIRDOSE 3.0 software. The highest 76Br concentrations were found in lungs, after a correction for the air volume in this organ. The lungs received the highest absorbed dose (mGy/MBq, mean+/-maximum error), 0.84+/-0.16, followed by liver, 0.74+/-0.28, and small intestine, 0.55+/-0.05, while the effective dose equivalent was 0.41+/-0.03 mSv/MBq. The PET imaging properties of 76Br in a two-dimensional 2D PET camera, including central area resolution and scattering effects, were investigated in phantoms and compared to those of 18F. In a 0.97 g/cm3 material, approximating soft tissue density, the FMHW ("full width at half-maximum") value of the point spread function was 7.7+/-0.2 mm for 76Br and 6.0+/-0.1 mm for 18F. In conclusion, radioimmuno PET using 76Br-labeled antibodies resulted in a fairly even distribution of the radiation dose, where the highest absorbed organ doses were only about two to three times higher than the mean absorbed body dose. The high energy beta+ spectrum in the 76Br decay had only minor effects on the resolution, but may decrease the quantification accuracy, especially in organs with a lower density such as a lung.

Unlabelled: The potential of a 76Br-labeled anti-carcinoembryonic antigen monoclonal antibody (MAb), 38S1, as tumor-imaging agent for PET was investigated in a comparative experimental study with [18F]fluorodeoxyglucose ([18F]FDG) and L-[methyl-11C]methionine ([11C]Met)., Methods: The three radiotracers were administered to nude rats carrying subcutaneous xenografts or liver metastases from a human colonic carcinoma. Tracer biodistribution was evaluated by PET imaging and radioactivity measurement of dissected tissues and also by whole-body autoradiography for subcutaneous xenografts., Results: For PET imaging of subcutaneous tumors, 76Br-38S1 proved superior to the other radiotracers. Tumor-to-tissue ratios were, except for the tumor-to-blood ratio, generally higher for 76Br-labeled MAb than for [18F]FDG and [11C]Met. Liver metastases were imaged with PET using both 76Br-38S1 and [18F]FDG, and the metastases-to-liver ratios of dissected samples were not significantly different for the two radiotracers., Conclusion: The tumor-imaging capacity of 76Br-labeled MAb 38S1 was superior to [18F]FDG and [11C]Met in the subcutaneous tumor model, whereas 76Br-38S1 and [18F]FDG were equally successful for the identification of liver metastases.

Unlabelled: Bromine-76 is potentially useful as a radiolabel for monoclonal antibodies (MAbs) in PET imaging. The purpose of the present study was to evaluate the 76Br-labeled anticarcinoembryonic antigen (-CEA) MAb 38S1 as a tumor imaging agent in an experimental tumor model and to study the pharmacokinetics of 76Br-38S1 in comparison with 125I-38S1., Methods: Nude rats carrying human colon carcinoma xenografts were co-injected with directly labeled 76Br-38S1 and 125I-38S1. Biodistribution of labeled 38S1 was monitored for 4 days after administration, in the case of 76Br activity, including PET imaging. In addition, catabolism of radiolabeled MAbs was analyzed by gel filtration chromatography of blood plasma and homogenized tissues., Results: Tumor sites could be readily identified by PET imaging from 46 hr after administration of 76Br-38S1 and onwards. The concentration of 76Br activity in tumors, blood and most normal tissues was higher than the corresponding 125I concentration at all time points. This was mainly due to catabolism of radiolabeled MAb, resulting in free radiohalides, of which 76Br- was retained in contrast to the rapidly excreted 125I- ion., Conclusion: Bromine-76-labeled anti-CEA MAbs may be applied for experimental tumor imaging with PET.

4-[76Br]bromodexetimide and its inactive enantiomer 4-[76Br]bromolevetimide were prepared via electrophilic bromodesilylation using chloramine-T and no-carrier-added (NCA) [76Br]NH4. In vitro, Bmax measured on rat cortex membranes were 3.7 +/- 0.2 and < 0.07 pmol/mg protein for 4-[76Br]bromodexetimide and 4-[76Br]bromolevetimide, respectively. The kD of 4-[76Br]bromodexetimide was 1.9 +/- 0.3 nM. In vivo studies in rats showed specific uptake of 4-[76Br]bromodexetimide in cortex, striatum, thalamus and hippocampus. No specific uptake was observed with 4-[76Br]bromolevetimide. With [76Br]bromodexetimide, positron emission tomography (PET) studies in primates demonstrated a preferential accumulation of the radioactivity in the cortex and striatum which was displaced to the level of cerebellum by dexetimide. With 4-[76Br]bromolevetimide, the radioactivity concentrations in the cortex and striatum were similar to that of cerebellum.

Unlabelled: The heterogeneity of tumor uptake is likely to substantially limit the effectiveness of metaiodobenzylguanidine (MIBG) therapy. This study was done to establish whether metabromobenzylguanidine (MBBG) can target neuroendocrine tumors and to provide intratumor biodistribution and uptake information in comparison to MIBG., Methods: MBBG and MIBG tumor uptake and kinetic studies were performed in experimental PC-12 pheochromocytoma grown in nude mice. Intratumor distribution studies were performed using autoradiography and secondary ion mass spectrometry (SIMS) microscopy, because the latter technique can detect and potentially quantify both drugs concomitantly within the same tumor specimen., Results: MBBG uptake in PC12 tumors was early (2 hr) and intense (80% ID/g). Retention values were similar for both drugs 24 hr postinjection. At the cellular level, MBBG mostly accumulated in the cytosol. At the multicellular level, cells exhibited staining, but in many areas, SIMS images of both drugs were not spatially correlated., Conclusion: MBBG targeted experimental pheochromocytoma efficiently with high early uptake values. Bromine-76-MBBG is a promising means of imaging and quantifying tumor uptake with PET. Both drugs were localized in the cytosol, but the correlation between the two distributions, as assessed by the values of the standardized local concentrations, was weak although significant multicellularly.

[76Br]-meta-Bromobenzylguanidine ([76Br]MBBG) was prepared from the iodinated analog (MIBG) and [76Br]NH4 using a Cu(+)-assisted halogen exchange reaction. [76Br]MBBG was produced in a 60-65% radiochemical yield with a specific activity of 20 MBq/nmol. In rats, biodistribution kinetic studies showed a high uptake of [76Br]MBBG in heart tissues with its maximum of 5% ID/S at 2 h p.i.; whereas 4 h p.i., the maximum of the heart-to-lung concentration ratio of 8 was observed. Metabolic studies in rats indicated that [76Br]MBBG was rapidly metabolized in plasma. However in heart tissue, 25 h p.i., 85% of the radioactivity still represented unchanged radiotracer. Pharmacological studies in rats showed that the myocardial uptake of [76Br]MBBG was similar to that of norepinephrine. After pretreatment of the rats, the uptake of [76Br]MBBG was reduced 4 h p.i. to the following values: after desipramine (DMI) to 37%, after dexamethasone (DXM) to 88% and after 6-hydroxydopamine (6-OHDA) to 16%. These preliminary results suggest that [76Br]MBBG can be useful for the assessment of heart catecholamine reuptake disorders with PET.

A positron-emitting isotope of bromine, 76Br, with a half-life of 16.2 h, was produced using the reaction natBr(p, xn)76Kr. Labelling of mouse epidermal growth factor (EGF) with 76Br was optimized, using the chloramine-T method, obtaining a maximal radiochemical yield of 53%. In tests with receptor-rich, cultured glioma cells, [76Br]EGF and [125I]EGF bound equally well. A study of the distribution and stability of [76Br]EGF and [125I]EGF in normal rat was carried out. The distribution of both radioisotopes was similar, however, the percentage of 76Br bound to the high molecular weight fraction in the plasma, liver and kidney was greater than that of 125I.

Published data were collected on clearance of 82Br, 24Na, inulin, and the ligands CaNa2-EDTA and CaNa3-DTPA from plasma of rats, dogs, and adult men. Data were restructured to a common base and reanalyzed using a two-compartment open-system kinetic model with an outlet from plasma to urinary excretion or from interstitial fluid to deposition in tissues. This was used to obtain transfer rates, distribution volumes, renal clearance, tracer content of interstitial fluid, and cumulative urinary excretion. The validity of the approach was demonstrated by good agreement of the calculated distribution volumes and renal clearances of the selected tracers with published values obtained by other analytical methods. The values of the parameters of the plasma curves and the transfer rates for EDTA and DTPA in the animals were combined with physiological data to evaluate the kinetic parameters of those substances in man. The human kinetic parameters of the ligands predicted from rat or dog data differed, on the average, from the values calculated from human data by +/- 13 and +/- 38%, respectively. The effective concentration of EDTA or DTPA in body fluids from time of injection to complete excretion and the mean concentration for the first 360 min after injection was calculated to be about four times greater in man than in rats and 3.5 times greater than in dogs for equimolar amounts injected. Based on the pharmacokinetics of DTPA, chelation therapy immediately after an actinide accident involving inhalation or extensive skin damage will be more efficient and more effective if a fraction of the standard clinical ZnNa3-DTPA dosage is administered every few hours instead of as a single daily injection.