Dirk Tourwé

A click approach to structurally diverse conjugates containing a central di-1,2,3-triazole metal chelate.

Assemble & chelate: Click chemistry enables the efficient and selective synthesis of structurally diverse conjugates containing a central di‐1,2,3‐triazole chelator for complexation with [99mTc(CO)3]+. Use of appropriate building blocks allows the modulation of pharmacological relevant characteristics of the conjugate, or the introduction of secondary probes suitable for imaging modalities other than single photon emission computed tomography (SPECT).

Bis(thiosemicarbazones) as bifunctional chelators for the room temperature 64-copper labeling of peptides

A range of new carboxylate functionalised bis(thiosemicarbazone) ligands and their Cu(II) complexes have been prepared, fully characterised and radiolabeled in high yield with both (64)Cu and (99m)Tc. Conjugation to a bombesin derivative was achieved using standard solid phase synthetic methodologies and the (64)Cu-labeled conjugate was shown to have good tumour uptake in mice with xenografted PC-3 tumours.

Molecular Assembly of Multifunctional 99mTc Radiopharmaceuticals Using Clickable Amino Acid Derivatives

Synthetic strategies that enable the efficient and selective combination of different biologically active entities hold great promise for the development of multifunctional hybrid conjugates useful for biochemical and medical applications. Starting from side‐chain‐functionalized N(α)‐propargyl lysine derivatives, conjugates containing a 99mTc‐based imaging probe for SPECT and two different moieties (e.g., tumor‐targeting vectors, pharmacological modifiers, affinity tags, or second imaging probes) can be assembled using the CuI‐catalyzed alkyne–azide cycloaddition in efficient one‐pot protocols. This strategy was successfully applied to the preparation of a 99mTc‐labeled conjugate comprising a tumor‐targeting peptide sequence (bombesin(7–14)) and a low‐molecular‐weight albumin binder, a pharmacological modifier that prolongs the blood circulation time of the conjugate. Evaluation of the conjugate in vitro and in vivo provided promising results for its use as an imaging agent for the visualization of tumors positive for the gastrin‐releasing peptide receptor. The methodology presented herein provides an attractive synthetic tool for the preparation of multifunctional 99mTc‐based radiopharmaceuticals with significant potential for a multitude of applications.

Synthesis of Fused 3-Aminoazepinones via Trapping of a New Class of Cyclic Seven-Membered Allenamides with Furan

Novel tricyclic tetrahydroazepinones were synthesized via an in situ Diels-Alder reaction of furan with cyclic allenamides. These reactive intermediates are the first examples of cyclic seven-membered allenamides and were prepared starting from N-(2-chloroallyl)-2-allylglycine derivatives via ring-closing metathesis followed by dehydrochlorination. The trapping of the intermediate cycloallene with furan occurred endo- and regioselectively and provided a convenient entry into new building blocks for medicinal chemistry. The diastereoselectivity of the cycloaddition was confirmed using quantum chemical computations.

Highly Diastereoselective Synthesis of 1-Carbamoyl-4-aminoindoloazepinone Derivatives via the Ugi Reaction

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component reaction (Ugi-3CR) was developed to present trisubstituted indoloazepinones in good yields and excellent diastereomeric excess.

[3H]IVDE77, a novel radioligand with high affinity and selectivity for the insulin-regulated aminopeptidase

The hexapeptide angiotensin IV (Ang IV) induces diverse biological effects such as memory enhancement and protection against ischemic stroke. Studies on the mechanism of Ang IV however are hampered by its instability and its lack of selectivity. The high-affinity binding site for Ang IV is the insulin-regulated aminopeptidase (IRAP, EC 3.4.11.3), but Ang IV also acts as a weak agonist for the Ang II-receptor (AT1), implying the need for stable and highly selective Ang IV-analogues. Here we present the screening of novel Ang IV-analogues, selected on basis of high affinity for IRAP, high selectivity (compared to aminopeptidase N and the AT1 receptor) and resistance against proteases. The selected compound IVDE77 possesses a number of advantages compared to Ang IV: (i) it has a 40 times higher affinity for IRAP (Ki 1.71 nM), (ii) it does not activate the AT1 receptor, (iii) it is easily radiolabeled with tritium and (iv) it is resistant to proteolysis, even in human plasma. In addition, pre-treatment of intact CHO-K1 cells with IVDE77 led to a virtually complete inhibition of subsequent intracellular accumulation of [(3)H]IVDE77-IRAP complexes. IVDE77 thus represents the first Ang IV-analogue able to abolish IRAP-availability completely at the cell surface in vitro. In summary, IVDE77 is a useful tool for the detection of IRAP under physiological conditions, and may contribute to elucidating the mechanism of Ang IV to ascertain which functions are IRAP-dependent.

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.