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The organometallic technetium-99m tricarbonyl core, [ 99m Tc][Tc(CO) 3 (H 2 O) 3 ] + , is a versatile precursor for the development of radiotracers for single photon emission computed tomography (SPECT). A drawback of the 99m Tc-tricarbonyl core is its lipophilicity, which can influence the pharmacokinetic properties of the SPECT imaging probe. Addition of polar pharmacological modifiers to 99m Tc-tricarbonyl conjugates holds the promise to counteract this effect and provide tumor-targeting radiopharmaceuticals with improved hydrophilicities, e.g., resulting in a favorable fast renal excretion in vivo. We applied the "Click-to-Chelate" strategy for the assembly of a novel 99m Tc-tricarbonyl labeled conjugate made of the tumor-targeting, modified bombesin binding sequence [Nle 14 ]BBN(7-14) and the carbohydrate sorbitol as a polar modifier. The 99m Tc-radiopeptide was evaluated in vitro with PC-3 cells and in Fox-1 nu mice bearing PC-3 xenografts including a direct comparison with a reference conjugate lacking the sorbitol moiety. The glycated 99m Tc-tricarbonyl peptide conjugate exhibited an increased hydrophilicity as well as a retained affinity toward the Gastrin releasing peptide receptor and cell internalization properties. However, there was no significant difference in vivo in terms of pharmacokinetic properties. In particular, the rate and route of excretion was unaltered in comparison to the more lipophilic reference compound. This could be attributed to the intrinsic properties of the peptide and/or its metabolites. We report a novel glycated (sorbitol-containing) alkyne substrate for the "Click-to-Chelate" methodology, which is potentially of general applicability for the development of 99m Tc-tricarbonyl based radiotracers displaying an enhanced hydrophilicity.

An intriguing target involved in several pathophysiological processes is the 18 kDa translocator protein (TSPO), of which exact functions remained elusive until now. A single nucleotide polymorphism in the TSPO gene influences the binding affinity of endogenous and synthetic TSPO ligands by facilitating a lower-affinity conformation, which modifies a potential ligand binding site, ultimately leading to a binding profile classification according to each genotype. For instance, some clinical effects of the distinctive binding affinity profile of cholesterol toward the TSPO of individuals with different genotypes have been extensively discussed. Therefore, we conducted an investigation based on a radioligand binding assay, to determine the inhibition constants of some reported endogenous TSPO ligands (diazepam binding inhibitor and protoporphyrin IX), as well as synthetic ligands (disulfiram and derivatives). We observed no dependency of the polymorphism on the binding affinity of the evaluated endogenous ligands, whereas a high dependency on the binding affinity of the tested synthetic ligands was evident.

The tracer [[11C] meta -Hydroxyephedrine ([[11C] m HED) is one of the most applied PET tracers for cardiac imaging, whose radiosynthesis was already reported in 1990. While not stated in the literature, separation difficulties and an adequate formulation of the product are well known challenges in its production. Furthermore, the precursor (metaraminol) is also a substrate for the norepinephrine transporter, and can therefore affect the image quality. This study aims at optimizing the synthetic process of [[11C] m HED and investigating the effect of the apparent molar activity (sum of m HED and metaraminol) in patients and animals. The main optimization was the improved separation through reverse phase-HPLC by a step gradient and subsequent retention of the product on a weakly-cationic ion exchange cartridge. The µPET/µCT was conducted in ten rats (ischemic model) and the apparent molar activity was correlated to the VOI- and SUV-ratio of the myocardium/intra-ventricular blood pool. Moreover, nine long-term heart transplanted and five Morbus Fabry patients underwent PET and MRI imaging for detection of changes in the sympathetic innervation. In summary, the fully-automated synthesis and optimized purification method of [[11C] m HED is easily applicable and reproducible. Moreover, it was shown that the administered apparent molar activities had a negligible effect on the imaging quality.