In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography

Development of hypoxia-targeted therapies has stimulated the search for clinically applicable noninvasive markers of tumour hypoxia. Here, we describe the validation of [18F]fluoroetanidazole ([18F]FETA) as a tumour hypoxia marker by positron emission tomography (PET). Cellular transport and retention of [18F]FETA were determined in vitro under air vs nitrogen. Biodistribution and metabolism of the radiotracer were determined in mice bearing MCF-7, RIF-1, EMT6, HT1080/26.6, and HT1080/1-3C xenografts. Dynamic PET imaging was performed on a dedicated small animal scanner. [18F]FETA, with an octanol–water partition coefficient of 0.16±0.01, was selectively retained by RIF-1 cells under hypoxia compared to air (3.4- to 4.3-fold at 60–120 min). The radiotracer was stable in the plasma and distributed well to all the tissues studied. The 60-min tumour/muscle ratios positively correlated with the percentage of pO2 values <5 mmHg (r=0.805, P=0.027) and carbogen breathing decreased [18F]FETA-derived radioactivity levels (P=0.028). In contrast, nitroreductase activity did not influence accumulation. Tumours were sufficiently visualised by PET imaging within 30–60 min. Higher fractional retention of [18F]FETA in HT1080/1-3C vs HT1080/26.6 tumours determined by dynamic PET imaging (P=0.05) reflected higher percentage of pO2 values <1 mmHg (P=0.023), lower vessel density (P=0.026), and higher radiobiological hypoxic fraction (P=0.008) of the HT1080/1-3C tumours. In conclusion, [18F]FETA shows hypoxia-dependent tumour retention and is, thus, a promising PET marker that warrants clinical evaluation

Synthesis and evaluation of (S)-[F-18]-fluoroethylcarazolol for in vivo beta-adrenoceptor imaging in the brain

The beta-adrenergic receptor ligand (S)-4-(3-(2'-[F-18]-fluoroethylamino)-2-hydroxypropoxy)-carbazol ((S)-[F-18]-fluoroethylcarazolol) was prepared by reaction of [F-18]-fluoroethylamine with the corresponding (S)-epoxide and was evaluated in rats by studying its pharmacokinetics and its binding profile both in vitro and in vivo. In vitro, (S)-fluoroethylearazolol binds preferentially to beta-adrenoceptors (pK(i) = 9.3 for beta(1) and 9.4 for beta(2)) and has less affinity to 5HT(1A) and 5HT(1D) receptors (pK(i) = 6.7 and 5.2). In vivo, standard uptake values (SUVs) up to 0.63 +/- 0.07 in cortical regions were found after 60 min. Metabolites (90%) appeared within 10 min in plasma, whereas, in brain 70-75% parent compound was found after 60 min. Clearance from plasma occurred within 5 min. Cerebral uptake could be blocked by 'cold' fluoroethylearazolol in every region, except medulla. Uptake was also blocked by propranolol and pindolol, but not by WAY 100635. ICI 89406 hardly lowered [F-18] levels in brain. ICI 118551 reduced uptake of [F-18] in cerebellum (mainly 132) by 30%. Specific binding (tissue minus medulla values) in various brain regions corresponded with those observed for [F-18]-fluorocarazolol (r(2) = 0.95) and with in vitro beta-adrenoceptor densities (r(2) = 0.76). Autoradiography using phosphor images of (S)-[F-18]-fluoroethylcarazolol in rat brain showed the characteristic binding pattern of beta-antagonists, while propranolol treatment resulted in low and homogenous uptake. Regional tissue minus medulla values corresponded with in vitro P-adrenoceptor densities (r(2) = 0.77). We conclude that (S)-[F-18]-fluoroethylearazolol is a high affinity ligand that binds specifically to cerebral beta-adrenoceptors in vivo and may be of use for P-adrenoceptor imaging in the brain with PET. (C) 2002 Elsevier Science Ltd. All rights reserved

Coercion and Resistance in the Colonial Market: Cotton in Britain’s African Empire

Throughout the nineteenth century, the American South was the world’s leading producer of raw cotton. European — especially British — textile firms used American cotton to supply the world with cheap manufactured cloth. The African continent was on the periphery of this transatlantic circuit: forced into slavery and transported to the Americas, African peoples supplied much of the agricultural labour on which the cotton industry rested, but the African continent itself remained isolated from the expanding reach of the ‘empire of cotton’

Synthesis and evaluation of 18

Two carbonic anhydrase IX (CA IX) inhibitors were radiolabeled with (18)F, and evaluated for imaging CA IX expression. Despite good affinity for CA IX and excellent plasma stability, uptake of both tracers in CA IX-expressing HT-29 tumor xenografts in mice was low. (18)F-FEC accumulated predominately in the liver and nasal cavity, whereas a significant amount of (18)F-U-104 was retained in blood. Due to minimal uptake in HT-29 tumors compared to other organs/tissues, these two tracers are not suitable for use for CA IX-targeted imaging