Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

Folic acid, also known as vitamin B9, is the oxidized form of 5,6,7,8-tetrahydrofolate, which serves as methyl- or methylene donor (C1-building blocks) during DNA synthesis. Under physiological conditions the required amount of 5,6,7,8-tetrahydrofolate for survival of the cell is accomplished through the reduced folate carrier (RFC). In contrast, the supply of 5,6,7,8-tetrahydrofolate is insufficient under pathophysiological conditions of tumors due to an increased proliferation rate. Consequently, many tumor cells exhibit an (over)expression of the folate receptor. This phenomenon has been applied to diagnostics (PET, SPECT, MR) to image FR-positive tumors and on the other hand to treat malignancies related to a FR (over)expression. Based on this concept, a new 18F-labeled folate for PET imaging has been developed and was evaluated in vivo using tumor-bearing mice. The incorporation of oligoethylene spacers into the molecular structure led to a significant enhancement of the pharmacokinetics in comparison to previously developed 18F-folates. The liver uptake could be reduced by one sixth by remaining a tumor uptake of 3%ID/g leading to better contrast ratios. Encouraged by these results, a clickable 18F-labeled serine-based prosthetic group has been synthesized, again with the idea to improve the metabolic and pharmacokinetic profile of hydrophilic radiotracers. Therefore, an alkyne-carrying azido-functionalized serine derivative for coupling to biomolecules was synthesized and a chlorine leaving group for 18F-labeling, which could be accomplished using a microwave-assisted synthesis, a [K⊂2.2.2]+/carbonate system in DMSO. Radiochemical yields of 77±6% could be achieved.rnThe promising results obtained from the FR-targeting concept in the diagnostic field have been transferred to the boron neutron capture therapy. Therefore, a folate derivative was coupled to different boron clusters and cell uptake studies were conducted. The synthesis of the folate-boron clusters was straightforward. At first, a linker molecule based on maleic acid was synthesized, which was coupled to the boron cluster via Michael Addition of a thiol and alkene and subsequently coupled to the targeting moiety using CuAAC. The new conjugates of folate and boron clusters led to a significant increase of boron concentration in the cell of about 5-times compared to currently used and approved boron pharmaceuticals. rnMoreover, azido-folate derivatives were coupled to macromolecular carrier systems (pHPMA), which showed an enhanced and specific accumulation at target sites (up to 2.5-times) during in vivo experiments. A specific blockade could be observed up to 30% indicating an efficient targeting effect. A new kind of nanoparticles consisting of a PDLLA core and p((HPMA)-b-LMA)) as surfactants were developed and successfully radiolabeled via 18F-click chemistry in good RCYs of 8±3%rnThe nanoparticles were obtained via the miniemulsion technique in combination with solvent evaporation. The 18F-labeled nanoparticles were applied to in vivo testing using a mouse model. PET imaging showed a “mixed” biodistribution of low molecular weight as well as high molecular weight systems, indicating a partial loss of the 18F-labeled surfactant.rnIn conclusion, the presented work successfully utilized the FR-targeting concept in both, the diagnostic field (PET imaging) and for therapeutic approaches (BNCT, drug delivery systems). As a result, the high potential of FR-targeting in oncological applications has been shown and was confirmed by small animal PET imaging.rn

Pyrene derivatives as donors and acceptors

Pyrene derivatives as donors and acceptorsrnrnAlmost 200 years have passed since pyrene was first discovered, and to this day it garners unbroken interest by chemists around the world. One of the most fascinating areas of pyrene chemistry is its selective functionalization, since it is still currently a challenge to specifically functionalize different positions on the molecule.[1]rnIn this work, two new patterns of pyrene substitution have been developed. Under suitable conditions, a fourfold bromination of 4,5,9,10 tetramethoxypyrene is possible to yield eightfold functionalized pyrenes. Based on these molecules a novel series of 1,3,4,5,6,8,9,10-substituted pyrene derivatives was achieved. Synthetic approaches to a non-quinoidal, strong pyrene-4,5,9,10-tetraone based acceptor have been discussed. It emerged that the chosen synthetic approach is suitable for intermediate acceptors, yet it failed very electron deficient pyrene derivatives. Donors based on 4,5,9,10-tetramethoxypyrene (2,7- and 1,3,6,8-substitued) have been prepared and studied as CT complexes. In the SFB/TR 49 these complexes were analyzed in the solid state. For the first time charge transfer in a non-TTF CT-complex was studied by HAXPES and NEXAFS.rnBased on the works of ZÖPHEL et al.[2] it was possible to obtain an asymmetric 4,9,10 substituted pyrene derivative. This was used as a building block to prepare a non-planar acceptor molecule as well as electron-rich rylene-type molecules. rnFinally, two separate series of molecules intended as emitters for OLEDs were presented. Thermally activated delayed fluorescence (TADF) in OLEDs attracted significant academic interest as it is considered a promising approach to improve the efficiency of fluorescent OLEDs.[3] Our molecules were designed to have a deep blue emission spectrum and a minimal singlet triplet energy gap (∆ES1->T1) while retaining a high fluorescence quantum yield ϕPL. The initial OD series has a small ∆ES1->T1, yet had an insufficient ϕPL for the use in OLEDs. The Py series emitters, in contrast, combine both desired properties and were successfully implemented in efficient OLED devices.rn[1]. T. M. Figueira-Duarte and K. Müllen, Chem. Rev., 2011, 111, 7260-7314.rn[2]. L. Zöphel, V. Enkelmann and K. Müllen, Org. Lett., 2013, 15, 804-807.rn[3]. H. Uoyama, K. Goushi, K. Shizu, H. Nomura and C. Adachi, Nature, 2012, 492, 234-238.