8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is an established radioligand for PET imaging of A1 adenosine receptors (A1R), but its application is complicated by rapid peripheral metabolism. To identify A1R ligands with improved properties, several new CPFPX derivatives were developed and evaluated by preclinical in vitro studies. The most promising compound showed significantly improved A1R affinity and selectivity compared to CPFPX and no formation of lipophilic metabolites. In addition, the corresponding radioligand [18F]1-NBX exhibited a high passive permeability and an A1R-specific distribution pattern with low non-specific binding in autoradiographic studies with rat brain slices. These findings identify [18F]1-NBX as a promising candidate for further preclinical evaluation as potential PET tracer for A1R imaging.

A novel indirect radiolabeling method for the radiofluorination of thiol-containing substrates based on Pd-catalyzed S-arylation was developed. The prosthetic group, 2-[18F]fluoro-5-iodopyridine, is easily accessible through a simple, minimalist radiofluorination technique. The versatility and practicality of the method were demonstrated by the successful synthesis of a novel PSMA-specific PET tracer, as well as 18F-labeling of glutathione, the Aβ oligomer-binding RD2 peptide, bovine serum albumin, and PSMA I&S. The approach enables fast, efficient, and robust labeling, making it highly suitable for the development of new PET tracers targeting various biomolecular structures.

To enable 18F-labeling of sensitive molecules under mild conditions, 1-alkylamino-7-[18F]fluoro-8-azaisatoic anhydrides ([18F]AFAs) were developed as new prosthetic groups for indirect radiofluorination. The [18F]AFAs were efficiently prepared within 15 min using readily accessible precursors and could be conjugated with a range of amines and alkyne- or azide-functionalized precursors to afford the corresponding 18F-labeled conjugates in high radiochemical conversions of up to 98%. The practical utility of the new prosthetic groups was confirmed by successful radiosynthesis of three 18F-labeled PSMA ligands with excellent in vivo stability and, in one case, promising imaging properties.

To visualize glycine transporter 1 (GlyT1) in the brain using PET imaging, the compounds [18F]ALX5407 and its corresponding methyl ester, [18F]ALX5406, were prepared via alcohol-enhanced copper-mediated radiofluorination and subjected to a preclinical evaluation. While [18F]ALX5407 demonstrated accumulation consistent with the GlyT1 distribution in rat brain slices, it showed no brain uptake in healthy rats. In contrast, the methyl ester [18F]ALX5406 rapidly entered the brain, where it was enzymatically converted into [18F]ALX5407, resulting in a regional accumulation pattern consistent with GlyT1-specific binding. Therefore, [18F]ALX5406 represents a promising PET tracer for preclinical in vivo imaging of GlyT1 in the brain.

O-([18F]Fluoroethyl)-L-tyrosine ([18F]FET) is a clinically established radiotracer for PET imaging of brain tumors, but its tumor uptake is limited by a relatively low affinity for its biological target LAT1. To identify radiotracers with improved affinity and tumor uptake, the meta-substituted [18F]FET analog m-[18F]FET and the methyl ester [18F]FET-OMe were developed and compared to [18F]FET. The results showed reduced in vitro uptake of [18F]FET-OMe by tumor cells and no advantages for in vivo imaging in a brain tumor model. In contrast, m-[18F]FET exhibited significantly improved in vitro uptake and accelerated in vivo tumor accumulation. As such, m-[18F]FET represents a promising alternative to [18F]FET for brain tumor imaging.

Prostate-specific membrane antigen (PSMA) represents a promising target for PET imaging of prostate cancer, as it is almost exclusively expressed in malignant prostate tumors. To improve PSMA-targeted PET imaging, a series of PSMA-binding radioligands were developed and preclinically evaluated. Among these, the compound [18F]JK-PSMA-7 was identified as a particularly promising candidate for the high-contrast visualization of small PSMA-positive lesions. The high diagnostic value of this radiotracer has also been confirmed by independent results summarized in more than 20 publications from various clinics worldwide, leading to its advancement into Phase 3 clinical trials.

To reduce the precursor amounts required for Cu-mediated radiofluorination, a series of new mediators for the 18F-labeling of aryl boronic and stannyl substrates was identified through a systematic evaluation of various copper complexes. Under optimized reaction conditions, application of these mediators significantly improved the 18F-labeling yields compared to conventional Cu(Py)4(OTf)2 despite the use of reduced precursor amounts. The practicality of the new mediators was demonstrated by the efficient production of several established and emerging PET tracers as well as transfer of the optimized protocol to an automated radiosynthesis module.

PET tracers for the visualization of tryptophan metabolic pathways can provide valuable information about various pathologies, including neurological disorders and cancer. In a preclinical evaluation of different 18F-labeled fluorotryptophans, 7-[18F]fluorotryptophan (7-[18F]FTrp) was identified as a metabolically stable radiotracer that enables a clear delineation of serotonergic brain areas as well as the melatonin-producing pineal gland in healthy rats. In addition, follow-up studies in animal models of neurodegenerative diseases demonstrated that 7-[18F]FTrp can not only visualize changes in serotonin and melatonin synthesis but also pathological alterations in the so-called kynurenine metabolic pathway. As such, this radiotracer represents a promising candidate for imaging pathological changes in tryptophan metabolism.

8-Cyclopentyl-3-(3-[18F]fluoropropyl)-1-propylxanthine ([18F]CPFPX) is an established radioligand for PET imaging of A1 adenosine receptors (A1R), but its application is complicated by rapid peripheral metabolism. To identify A1R ligands with improved properties, several new CPFPX derivatives were developed and evaluated by preclinical in vitro studies. The most promising compound showed significantly improved A1R affinity and selectivity compared to CPFPX and no formation of lipophilic metabolites. In addition, the corresponding radioligand [18F]1-NBX exhibited a high passive permeability and an A1R-specific distribution pattern with low non-specific binding in autoradiographic studies with rat brain slices. These findings identify [18F]1-NBX as a promising candidate for further preclinical evaluation as potential PET tracer for A1R imaging.