National survey on the natural radioactivity and 222Rn exhalation rate of building materials in The Netherlands.

The present study reports on results of a nation-wide survey on the natural radioactivity concentrations and Rn exhalation rates of the prevailing building materials in the Netherlands. In total 100 samples were taken and analyzed for the activity concentrations of Ra, Ra, Th, and K and for their Rn exhalation rate. The sampled materials consisted of gypsum products, aerated concrete, sand-lime and clay bricks, mortars and concrete, representing about 95% of the stony building materials used in the construction of Dutch homes. The laboratory analyses were performed according to two well-documented standard procedures, the interlaboratory reproducibility of which is found to be within 5% on average. The highest radionuclide concentrations were found in a porous inner wall brick to which fly ash was added. The second highest were clay bricks with average Ra and Ra levels around 40 Bq kg. Concrete and mortar show the highest exhalation rates with a fairly broad range of 1 to 13 microBq (kg s). Low natural radioactivity levels are associated with either natural gypsum (products) or gypsum from flue gas desulphurization units, and low exhalation rates with clay bricks. To evaluate the radiological impact the radioactivity concentrations in each sample were combined into a so-called dose factor, representing the absorbed dose rate in a room with a floor, walls and ceiling of 20 cm of the material in question. For that purpose, calculations with the computer codes MCNP, Marmer and MicroShield on the specific absorbed dose rates were incorporated in the paper. The results of these codes corresponded within 6% and average values were calculated at 0.90, 1.10, and 0.080 nGy h per Bq kg for the U series, the Th series, and K, respectively. Model calculations on the external dose rate, based on the incidence of the various building materials in 1,336 living rooms, are in accordance with measured data.

RP-HPLC separation of the diastereomers of technetium-99m labelled tropanes and identity confirmation using radio-LC-MS.

99mTc-TRODAT-1 (technetium(V)-oxo-2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]]amino]-ethanethiolato(3-)) and 99mTc-TRODAT-M, the 4-methylphenyl derivative of 99mTc-TRODAT-1, are at this moment being evaluated in clinical trials as imaging agents for the central nervous dopamine transporter system. Both compounds are formed as a mixture of two major diastereomers. As the tracer concentration in preparations for clinical investigations is very low (30-150 pmol/ml), identification of these 99mTc-complexes was, up to now, carried out indirectly using X-ray diffraction analysis of the corresponding rhenium complexes which can be synthesized in gram amounts. In this study, we developed a convenient and practical reversed phase HPLC-method for purification and isolation of the respective diastereomers of 99mTc-TRODAT-1 and three of its derivatives using mixtures of solvents which are compatible with biological studies, i.e. aqueous buffers and ethanol. Furthermore, direct identity confirmation of the 99mTc-complexes using radio-LC-MS was successfully elaborated.

Evaluation of 99mTc-MAMA-chrysamine G as an in vivo probe for amyloidosis.

To date, systemic amyloidosis is diagnosed histologically using Congo red staining or in vivo using iodine-123 labelled serum amyloid P component (123I-SAP) scintigraphy. We developed 99mTc-MAMA-CG, a 99mTc-labelled derivative of the lipophilic Congo red analogue chrysamine G (CG), as a possible alternative to 123I-SAP. In vivo 99mTc-MAMA-CG scintigraphy, performed in chickens with spontaneous joint amyloidosis, resulted as soon as 10 min after injection in scintigraphic images showing uptake of activity in amyloid-loaded organs (liver, joints). One of these chickens was studied also with 123I-SAP resulting in scintigraphic images revealing 123I-SAP binding to amyloid deposits in the liver. However, up to 11 h after injection no radioactivity was visible in the amyloid positive joints. In vitro autoradiography, performed on sections of chicken joints with Enterococcus faecalis induced amyloid arthropathy (chjAA), demonstrated the failure of 99mTc-MAMA-CG to bind significantly to amyloid deposits in the presence of 10 microM Congo red The specificity of 99mTc-MAMA-CG localisation was also established by the absence of 99mTc-MAMA-CG binding in non-amyloidotic organs in vitro and in vivo. 99mTc-MAMA-CG did not show any sign of acute toxicity. These findings establish the usefulness of 99mTc-MAMA-CG as a non-invasive in vivo diagnostic probe in chickens with amyloid arthropathy and suggest that it may also be applicable to human amyloidosis.

In vitro affinity of 99Tcm-labelled N2S2 conjugates of chrysamine G for amyloid deposits of systemic amyloidosis.

To date, systemic amyloidosis is diagnosed histologically in vitro using Congo red staining or in vivo using iodine-123 serum amyloid P component (123I-SAP) scintigraphy. 99Tcm-labelled derivatives of chrysamine G (CG), a lipophilic analogue of Congo red, were synthesized as potential tracer agents for direct and quantitative scintigraphic evaluation of amyloid deposits. To determine the affinity of 99Tcm-MAMA-CG, 99Tcm-Me4MAMA-CG and 99Tcm-MAMA-CG diethyl ester for amyloid, in vitro autoradiography was performed on sections of human kidney biopsy cylinders from kidneys with amyloid deposits (types AA, Alambda and Akappa) or control kidney tissue after incubation with the respective tracer agents. The binding of 99Tcm-MAMA-CG and its tetramethyl derivative was higher to kidney biopsy material with amyloid deposits of the AA, Alambda or Akappa type compared with control kidney tissue. This higher binding was prevented by the presence of 10 microM Congo red in the incubation medium. The diethyl ester of 9Tcm-MAMA-CG did not demonstrate increased binding to Congo red-positive kidney tissue. In conclusion, 99Tcm-MAMA-CG and 99Tcm-Me4MAMA-CG localize specifically to amyloid deposits in human kidney tissue, suggesting that these tracer agents may be applicable as specific targeting agents for diagnostic purposes in clinical amyloidosis.

99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease.

Chrysamine G (CG), an analogue of Congo red, is known to bind in vitro to the beta-amyloid protein (Abeta 10-43) and to homogenates of several regions of the brain of Alzheimer's disease (AD) patients. We synthesised a conjugate of 2-(acetamido)-CG with a bis-S-trityl protected monoamide-monoaminedithiol (MAMA-Tr(2)) tetraligand, which was efficiently deprotected and labelled with a 75% yield with technetium-99m, to obtain (99m)Tc-MAMA-CG. In mice, (99m)Tc-MAMA-CG was cleared mainly by the hepatobiliary system, resulting in a fast blood clearance. Brain uptake of (99m)Tc-MAMA-CG was low. Co-injection with the blood pool tracer iodine-125 human serum albumin ((125)I-HSA) demonstrated a brain/blood activity ratio for (99m)Tc-MAMA-CG that was significantly higher than that for (125)I-HSA (t test for dependent samples, P<0.02), indicating the ability of (99m)Tc-MAMA-CG to cross the blood-brain barrier. In vitro autoradiography demonstrated pronounced binding of (99m)Tc-MAMA-CG to beta-amyloid deposits in autopsy sections of the parietal and occipital cortex of an AD patient as compared with controls. Adding 10 microM Congo red during incubation displaced the binding of (99m)Tc-MAMA-CG. Congo red staining and autoradiography identified the same lesions. (99m)Tc-MAMA-CG seems to bind selectively to beta-amyloid deposition in human brain parenchyma and blood vessels in vitro and thus might be a lead compound for further development of a useful tracer agent for the in vivo diagnosis of Alzheimer's disease.

In vitro evaluation of N-(fluoro)isopropyl norephedrine as potential cardiac imaging agents for PET.

N-Isopropylnorephedrine (INE) and N-fluoroisopropylnorephedrine (FINE) were found to have a poor affinity for either beta-adrenoceptors and the norepinephrine carrier protein. The low affinity of both compounds for Uptake-1 is probably due to the introduction of a bulky substituent on the nitrogen atom. It is concluded that INE and FINE cannot be used for cardiac imaging with PET.

(S,S)- and (S,R)-1'-[18F]fluorocarazolol, ligands for the visualization of pulmonary beta-adrenergic receptors with PET.

The beta-adrenoceptor antagonist carazolol has been labelled with fluorine-18 in the isopropyl group via a reductive alkylation by [18F]-fluoroacetone of the corresponding (S)-desisopropyl compound according to a known procedure. The introduction of fluorine in the isopropyl group creates a new stereogenic centre resulting in the formation of (S,S)- and (S,R)-1'-[18F]fluorocarazolol, which were separated by HPLC. Tissue distribution studies were performed in male Wistar rats. Both the (S,S)- and (S,R)-diastereomers (S.A. 500-2000 Ci/mmol; 18.5-74 TBq/mmol) showed high uptake in lung and heart, which could be blocked by pretreatment of the animals with (+/-)-propranolol. No significant differences were observed between the biodistribution of the two diastereomers. Metabolite analysis showed a rapid appearance of polar metabolites in plasma, while at 60 min postinjection 92% and 82% of the total radioactivity in lung and heart was unmetabolized 1'-[18F]fluorocarazolol. In a PET-study with male Wistar rats, the lungs were clearly visualized and the pulmonary uptake was decreased after pretreatment of the animals with (+/-)-propranolol. The heart could not be visualized. Similar results were obtained in PET-studies with lambs.

N-[18F]-fluoroalkylation of noraporphines: microwave versus thermal treatment.

A comparable study of microwave versus thermal heating is described for the N-[18F]-fluoroalkylation of noraporphines. As compared to thermal treatment, different products were obtained during microwave treatment. Thermal treatment resulted in the loss of the protection of the catechol functionality of the noraporphines (O-deacylation), whereas during microwave treatment N-[18F]-fluoroalkylation was observed. The results described in this report might suggest that the influence of microwaves on chemical transformations is not exclusively thermal.

Synthesis of 6 alpha-[18F]fluoroprogesterone: a first step towards a potential receptor-ligand for PET.

6 alpha-[18F]Fluoroprogesterone 3 was prepared by the BF3.Et2O-catalyzed reaction of progest-5 alpha, 6 alpha-epoxy-3,20-bisketal 1 and [18F]fluoride as a possible route for the in vivo visualization of progesterone receptors by PET. The radiochemical yield of 3 was 25% (EOB) and the sp. act. was 5 MBq/mumol (100 Ci/mol, EOS).

Synthesis and evaluation of 1'-[18F]fluorometoprolol as a potential tracer for the visualization of beta-adrenoceptors with PET.

(+/-)-1'-[18F]Fluorometoprol 4 was prepared from desisopropylmetoprolol and [18F]fluoroisopropyl tosylate 2 with a radiochemical yield of 2% [corrected for decay to end of bombardment (EOB), synthesis time 90 min]. Synthon 2 was prepared from (S)-1,2-propanediol di(p-toluenesulfonate) in 45% radiochemical yield (EOB, 40 min). Compound 4 shows in two in vitro assays a similar affinity at beta-adrenoceptors (about 0.3 microM) as metoprolol 5, but with a slightly higher beta 1/beta 2-adrenoceptor selectivity ratio (48.6 vs 30.7). In vivo experiments with 4 showed almost no receptor-mediated uptake in the heart, probably because the affinity of (fluoro)metoprolol for the beta 1-adrenoceptors is too low for successful imaging. However, the in vitro experiments suggest that the fluoroisopropyl group is suitable for the synthesis of [18F]fluorinated beta 1-adrenergic receptor binding ligands.

Preclinical evaluation of a positron emitting progestin ([18F]fluoro-16 alpha-methyl-19-norprogesterone) for imaging progesterone receptor positive tumours with positron emission tomography.

Three 21-fluoro-progestins were investigated as potential imaging agents for the in vivo assessment of human progesterone receptor positive neoplasms with positron emission tomography. In competitive binding assays these compounds demonstrated high specificity, competing only for progesterone receptors. Binding to other steroid receptor types was negligible. Based on its high affinity binding, 21-fluoro-16 alpha-methyl-19-norprogesterone was selected for further evaluation in vivo. Tissue distribution studies in immature estrogen primed female rats revealed high uterine uptake of 21-[18F]fluoro-16 alpha-methyl-19-norprogesterone ([18F]FMNP). At 60 min after injection the ratio of uptake of radioactivity by uterine tissue to that of blood was 7. This ratio increased to 24 at 180 min. A selective decrease in uterine uptake was observed after administration of [18F]FMNP with excess unlabelled progestin. Rats bearing hormone responsive MT-W9A mammary adenocarcinomas were used to examine [18F]FMNP for tumour uptake. Animals were used irrespective of the phase of the estrous cycle. At 180 min the uterus to blood ratio and the tumour to blood ratio ranged from 3 to 20 and 3 to 17, respectively. Uterine and tumour tissue was assayed for cytosolic estrogen and progesterone receptors using a dextran-coated charcoal method and Scatchard plot analysis. The results indicate that the in vivo uptake of [18F]FMNP by uterine and mammary tumour tissue correlates well with the progesterone receptor concentration (rs = 0.98 and rs = 0.88, respectively). It is concluded that the uptake of [18F]FMNP by progesterone receptor positive tissue in vivo is primarily receptor related and that this uptake is attributable to the progesterone receptor. The study demonstrates the potential applicability of [18F]FMNP and positron emission tomography for imaging progesterone receptor positive neoplasms.

A fluorine-18 labeled progestin as an imaging agent for progestin receptor positive tumors with positron emission tomography.

The potential of the fluorine-18 labeled progestin 21-[18F]fluoro- 16 alpha-ethyl-19-norpregn-4-ene-3,20-dione [( 18F]FENP) as an imaging agent for the in vivo assessment of progestin receptor (PR) positive neoplasms with positron emission tomography has been investigated. Tissue distribution studies in immature estrogen primed female rats revealed high uptake of radioactivity, expressed as the differential absorption ratio, by uterine tissue. After simultaneous administration with unlabeled FENP, a significant decrease (83%) in uterine uptake was observed 60 min after injection. Uterine uptake was highly selective. The ratio of uptake of radioactivity by uterine tissue to that by blood was 39 at 180 min. In mice bearing transplanted Grunder strain mammary carcinomas tissue, distribution studies demonstrated a selective uptake of [18F]FENP by PR positive tumors. Pretreatment with unlabeled FENP caused a significant decrease (66%) in tumor uptake. Uptake by other tissues was not affected by the presence of unlabeled progestin. The ratio of uptake of radioactivity by tumor tissue to that by blood was 4.7 at 180 min. For FENP pretreated mice and mice bearing PR negative tumors, this ratio was 1.7 and 1.1, respectively. It is concluded that the uptake of [18F]FENP by uterine and by PR positive mammary tumor tissue in vivo is primarily receptor related, presumably to the PR. Furthermore, [18F]FENP appears to be suitable for imaging of PR positive human neoplasms with positron emission tomography.

Synthesis of [18F]fluoro-labeled progestins for PET.

The synthesis of 21-[18F]fluoro-16 alpha-methyl-19-norprogesterone, 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone, 21-[18F]fluoro-16 alpha-methylprogesterone and 21-[18F]fluoro-16 alpha-ethylprogesterone is described. These compounds are prepared with a specific activity greater than 200 TBq/mmol (5000 Ci/mmol) from the corresponding tosylates in 10% radiochemical yield (EOB). A remote controlled system has been developed for this synthesis.