T. de Groot

Synthesis of N-(2-[18F]fluoroethyl)-N'-methylthiourea : a hydrogen peroxide scavenger

N-(2-[18F]fluoroethyl)-N′-methylthiourea ([18F]FEMTU), a fluorine-18 labelled derivative of the hydrogen peroxide scavenger dimethlthiourea (DMTU), has been synthesized by reaction of 2-[18F]fluoroethylamine with methylisothiocyanate. 2-[18F]Fluoroethylamine was obtained in modest radiochemical yields (39±6%, mean±sd, n=5, decay corrected) by nucleophilic substitution with [18F]fluoride on N-[2-(p-toluenesulfonyloxy)ethyl]phthalimide followed by deprotection with hydrazine and distillation. The distilled 2-[18F]fluoroethylamine was trapped in CH2Cl2 and reacted with methyl-isothiocyanate to yield [18F]FEMTU that was purified by reversed phase HPLC. The total synthesis takes 150 min and provides [18F]FEMTU with a specific activity of 3.3±0.5 GBq/μmol (mean±sd, n=3) at end of synthesis, with an overall decay corrected radiochemical yield of 25±8% (mean±sd, n=5).

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.

Synthesis and evaluation of the 99mtc-complexes of l-cysteine acetyldiglycine (a hybrid of MAG3 and l,l-EC) and of l-β-homocysteine acetyldiglycine

Abstract ABSTRACT. l - Cysteine acetyldiglycine ( l- CAG2), a hybrid compound of l,l- EC and MAG3, and its l -β-homocysteine analogue l- HAG2 were synthesized. After labeling with 99m Tc, 99m Tc- l- CAG2 and 99m Tc- l- HAG2 gave two peaks on high performance liquid chromatography. Urinary excretion of both isomers of 99m Tc- l -CAG2 and 99m Tc- l -HAG2 was slower than for the “parent” complexes 99m Tc-MAG3 or 99m Tc- l,l- EC. Isomer B of 99m Tc- l -CAG2 showed pronounced kidney retention in mice (57% of ID in kidneys at 30 min postinjection), but further evaluation in baboon did not reproduce this phenomenon.

Synthesis of [18F]FA-4 and [11C]pipzA-4 as radioligands for the high affinity choline uptake system

We have prepared two radiolabelled analogues of hemicholinium-3 (HC-3) as potential in vivo tracers of the sodium dependent high affinity choline uptake (SDHAChU) system. Thus, 4-[1-hydroxy-2-(4-[18F]fluoromethylpiperidinyl)ethyl]-4′-[1-hydroxy-2-(4-methylpiperidinyl)ethyl]biphenyl ([18F]FA-4) and 4-[1-hydroxy-2-(4-[11C]methylpiperazinyl)ethyl]-4′-[1-hydroxy-2-(4-methylpiperidinyl)]biphenyl([11C] pipzA-4) have been synthesized. [18F]FA-4 was prepared by reaction of 4-[18F]fluoromethylpiperidine with 4-(α-bromoacetyl)-4′-(4-methylpiperidinylacetyl)-biphenyl followed by reduction of the keto groups to alcohols with NaBH4. The total synthesis time was 300 minutes and [18F]FA-4 was obtained with a specific activity of 5.6 GBq/μmol (EOS) and an overall decay corrected radiochemical yield of 3.1±0.6%. [11C]pipzA-4 was prepared by reaction of [11C]methyl triflate with 4-[1-hydroxy-2-piperazinyl)ethyl]-4′-[1-hydroxy-2-(4-methylpiperidinyl)ethyl]-biphenyl. The total synthesis time was 25 minutes and [11C]pipzA-4 was obtained with a specific activity of 13.7 GBq/μmol (EOS) and an overall decay corrected radiochemical yield of 19.5±2.2%. Copyright

Evaluation of 99mTc-complexes with novel monoamine diamide (MADA) thiolate tetraligands: L-cysteine acetyldiglycine diethyl ester and L-β-methylhomocysteinate acetyldiglycine ethyl ester

Compounds with a monoamine diamide (MADA) thiolate tetraligand structure (L-cysteine acetyldiglycine diethyl ester, L-CAG2D and L-β-methylhomocysteinate acetyldiglycine ethyl ester, L-HAG2ME) were synthesized and labelled with 99m Tc to investigate the 99m Tc-complexation characteristics of these tetraligands On reversed-phase HPLC, 99m Tc-L-CAG2D and 99m Tc-L-HAG2ME each give two peaks, probably isomers. During electrophoresis, all isomers migrate towards the anode indicating a net anionic charge. Octanol-buffer partition coefficients were respectively -0.47 and -0.05 for the isomers of 99m Tc-L-CAG2D and-0.51 and -0.32 for the isomers of 99m Tc-L-HAG2ME. In addition, brain uptake of all HPLC-isolated isomers was low and did not exceed 0.1% of injected dose at 2 min, 10 min or 30 min post injection. It may be concluded that the MADA-type ligands lose their amine proton upon complexation with 99m Tc resulting in hydrophilic, negatively charged 99m Tc-complexes which do not exhibit significant brain uptake in mice.