No abstract

Owing to its optimal nuclear properties, ready availability, low cost and favourable dosimetry, (99m)Tc continues to be the ideal radioisotope for medical-imaging applications. Bifunctional chelators based on a tetraamine framework exhibit facile complexation with Tc(V)O(2) to form monocationic species with high in vivo stability and significant hydrophilicity, which leads to favourable pharmacokinetics. The synthesis of a series of 1,4,8,11-tetraazaundecane derivatives (01-06) containing different functional groups at the 6-position for the conjugation of biomolecules and subsequent labelling with (99m)Tc is described herein. The chelator 01 was used as a starting material for the facile synthesis of chelators functionalised with OH (02), N(3) (04) and O-succinyl ester (05) groups. A straightforward and easy synthesis of carboxyl-functionalised tetraamine-based chelator 06 was achieved by using inexpensive and commercially available starting materials. Conjugation of 06 to a potent bombesin-antagonist peptide and subsequent labelling with (99m)Tc afforded the radiotracer (99m)Tc-N4-BB-ANT, with radiolabelling yields of >97% at a specific activity of 37 GBq micromol(-1). An IC(50) value of (3.7+/-1.3) nM was obtained, which confirmed the high affinity of the conjugate to the gastrin-releasing-peptide receptor (GRPr). Immunofluorescence and calcium mobilisation assays confirmed the strong antagonist properties of the conjugate. In vivo pharmacokinetic studies of (99m)Tc-N4-BB-ANT showed high and specific uptake in PC3 xenografts and in other GRPr-positive organs. The tumour uptake was (22.5+/-2.6)% injected activity per gram (% IA g(-1)) at 1 h post injection (p.i.). and increased to (29.9+/-4.0)% IA g(-1) at 4 h p.i. The SPECT/computed tomography (CT) images showed high tumour uptake, clear background and negligible radioactivity in the abdomen. The promising preclinical results of (99m)Tc-N4-BB-ANT warrant its potential candidature for clinical translation.

The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models.

The synthesis of heterocyclic compounds containing the 7-membered ring system [1,4]diazepane-2,5-dione is described. The aim of this study was to elaborate the solid phase and solution synthesis of eight representatives of the cyclic scaffold and to investigate their chemical stability and their conformational properties. The solid phase synthesis was performed on aminomethyl polystyrene resin using 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid as a backbone linker system (BAL-linker). After attachment of the α-and β-amino acid and deprotection of the amino function, the dipeptide ester was obtained. The molecule was cyclized on the solid support by treatment with NaOMe in MeOH/NMP. The product was cleaved from the resin by TFA. For the solution pathway the linear dipeptides were synthesized by coupling of the BOCprotected L-α-amino acid with the β 2 -amino acid ester (EDC/HOBT). After N -and C-terminal deprotection of the dipeptide, the linear species was cyclized with EDC/HOBT at a concentration of 3 mM in DMF. The products showed high chemical stability after storage in DMSO at room temperature for weeks. The x-ray and two dimensional NMR investigations were performed to investigate the conformation of the molecules. Three types of configuration could be distinguished by NMR, depending on the substitution pattern of the cyclic compounds. The x-ray results confirmed the NMR observations. In general the 7-membered rings showed rigidity, thus they could represent optimal scaffolds for new receptor ligands.

Dedicated to Professor D. Srehuck on the occasion of his 60th birthday 3-Hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran-2-ylidene)-and 2-cyano-2-(tetrahydropyran-2-y1idene)acetamides with N-alkyl and N-aryl substituents have been synthesized in three steps from cyanoacetic acid. Their conformations were investigated by X-ray crystallography and 'H-NMR ROESY spectroscopy at room temperature. The enolic compounds 1-3 adopt an extended conformation stabilized by a strong intramolecular 0 -H ... O=C bond both in the solid state and in (D,)DMSO solution. In contrast, the structure of the cyclic derivatives 5a,bbSa,b is solvent-dependent. In the solid state and in CDCI, solution, the compounds adopt an extended conformation of type I or 111, while, in (D,)DMSO solution, their structures undergo time-dependent (Z)/(E)-isomerization structures (of type 11 or IV). This observation is compatible with a dipolar transition state of rotation. The kinetics of the isomerization are controlled by the N-substituent, the N-(r-Bu) derivatives 7a and 7b having the highest barrier of rotation around the C = C bond. The whole body ofexperimental evidence together with the results of molecular-mechanics calculations with I -IV, indicate that, in DMSO, two (E)/(Z)-isomers with two conformations are present, and that they undergo interconversion at room temperature with four different constants. The very fast exchange rates k,,,, and k,,,,,, in the NMR time-scale might be responsible for the detection of only two isomers.