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Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [ 18 F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [ 18 F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [ 14 C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC 50 = 11 nM) by factors of 11 and 25, respectively, 1 (IC 50 = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [ 18 F] 1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D 7.4 result for [ 18 F] 1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [ 18 F] 1 compared to [ 18 F]FACH, the in vivo brain uptake of [ 18 F] 1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.

Overexpression of monocarboxylate transporters (MCTs) has been shown for a variety of human cancers (e.g., colon, brain, breast, and kidney) and inhibition resulted in intracellular lactate accumulation, acidosis, and cell death. Thus, MCTs are promising targets to investigate tumor cancer metabolism with positron emission tomography (PET). Here, the organ doses (ODs) and the effective dose (ED) of the first 18 F-labeled MCT1/MCT4 inhibitor were estimated in juvenile pigs. Whole-body dosimetry was performed in three piglets (age: ~6 weeks, weight: ~13-15 kg). The animals were anesthetized and subjected to sequential hybrid Positron Emission Tomography and Computed Tomography (PET/CT) up to 5 h after an intravenous (iv) injection of 156 ± 54 MBq [ 18 F]FACH. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity data. Time and mass scales were adapted to the human order of magnitude and the ODs calculated using the ICRP 89 adult male phantom with OLINDA 2.1. The ED was calculated using tissue weighting factors as published in Publication 103 of the International Commission of Radiation Protection (ICRP103). The highest organ dose was received by the urinary bladder (62.6 ± 28.9 µSv/MBq), followed by the gall bladder (50.4 ± 37.5 µSv/MBq) and the pancreas (30.5 ± 27.3 µSv/MBq). The highest contribution to the ED was by the urinary bladder (2.5 ± 1.1 µSv/MBq), followed by the red marrow (1.7 ± 0.3 µSv/MBq) and the stomach (1.3 ± 0.4 µSv/MBq). According to this preclinical analysis, the ED to humans is 12.4 µSv/MBq when applying the ICRP103 tissue weighting factors. Taking into account that preclinical dosimetry underestimates the dose to humans by up to 40%, the conversion factor applied for estimation of the ED to humans would rise to 20.6 µSv/MBq. In this case, the ED to humans upon an iv application of ~300 MBq [ 18 F]FACH would be about 6.2 mSv. This risk assessment encourages the translation of [ 18 F]FACH into clinical study phases and the further investigation of its potential as a clinical tool for cancer imaging with PET.

The adenosine A 2A receptor (A 2A R) is regarded as a particularly appropriate target for non-dopaminergic treatment of Parkinson's disease (PD). An increased A 2A R availability has been found in the human striatum at early stages of PD and in patients with PD and dyskinesias. The aim of this small animal positron emission tomography/magnetic resonance (PET/MR) imaging study was to investigate whether rotenone-treated mice reflect the aspect of striatal A 2A R upregulation in PD. For that purpose, we selected the known A 2A R-specific radiotracer [ 18 F] FESCH and developed a simplified two-step one-pot radiosynthesis. PET images showed a high uptake of [ 18 F] FESCH in the mouse striatum. Concomitantly, metabolism studies with [ 18 F] FESCH revealed the presence of a brain-penetrant radiometabolite. In rotenone-treated mice, a slightly higher striatal A 2A R binding of [ 18 F] FESCH was found. Nonetheless, the correlation between the increased A 2A R levels within the proposed PD animal model remains to be further investigated.

A small series of indol-3-yl-oxoacetamides was synthesized starting from the literature known N -(adamantan-1-yl)-2-(5-(furan-2-yl)-1-pentyl-1 H -indol-3-yl)-2-oxoacetamide ( 5 ) by substituting the 1-pentyl-1 H -indole subunit. Our preliminary biological evaluation showed that the fluorinated derivative 8 is a potent and selective CB₂ ligand with K i = 6.2 nM.