Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood–brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines—amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.

Toxicity of amphetamines: an update

Positron Emission Tomography (PET) experienced accelerated development and has become an established method for medical research and clinical routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clinical PET. The future development of the ⁶⁸Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, production and availability of ⁶⁸Ga, automation of the radiopharmaceutical production, progress of positron emission tomography technologies and image analysis methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chemistry. The review presents the prospects of the ⁶⁸Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents.

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Prospective of ⁶⁸Ga-radiopharmaceutical development.

Molecular imaging targeting peptide receptors.

⁶⁸Ge/⁶⁸Ga radionuclide generators have been investigated for almost fifty years now, since the cyclotron-independent availability of positron emitting ⁶⁸Ga via the ⁶⁸Ge/⁶⁸Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally approach a reliable level of ⁶⁸Ge/⁶⁸Ga generator designs, adequate to the modern requirements of radiometal labeling chemistry. ⁶⁸Ga radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the ⁶⁸Ge/⁶⁸Ga generator, now - more than ever, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved ⁶⁸Ge/⁶⁸Ga generator systems. The expected future broad clinical impact of ⁶⁸Ga-labelled radiopharmaceuticals - beyond the ⁶⁸Ga-DOTA-octreotide derivatives - for imaging tumors and many organs, on the other hand, identifies the development of sophisticated Ga(III) chelating structures to be a key factor. Today, open chain complexing agents have almost completely been displaced by macrocyclic DOTA and NOTA-derived conjugates. Structures of chelating moieties are being optimized in terms of thermodynamic stability and kinetic inertness, in terms of labeling efficacies at different, even acidic pH, and in terms of synthetic options towards bifunctionality, directed to sophisticated covalent coupling strategies to a variety of biologically relevant targeting vectors. Today, one may expect that the ⁶⁸Ge/⁶⁸Ga radionuclide generator systems could contribute to and facilitate the clinical impact of nuclear medicine diagnoses for PET in a dimension comparable to the established ⁹⁹Mo/⁹⁹(m)Tc generator system for SPECT.

The renaissance of the ⁶⁸Ge/⁶⁸Ga radionuclide generator initiates new developments in ⁶⁸Ga radiopharmaceutical chemistry.

Bifunctional chelating agents (BFCAs) are molecules which contain two different moieties: a strong metal chelating unit and a reactive functional group. The latter is directed to react with amines, thiols, alcohols or other reactive molecules to form stable covalent bonds while the chelating moiety is able to strongly coordinate a metal ion. In this way, it is possible to label a molecule of interest (e.g. an antibody or a peptide) with a metal or a radioactive metal ion. Of all the ligands reported so far, those based on a polyamino polycarboxylic structure are most efficient and are widely employed for the chelation of metal ions. The resulting metal complexes have found a broad range of applications in chemistry, biology and medicine. Diagnostic imaging (MRI, SPECT, PET), molecular imaging, tumour therapy and luminescent materials are only a few examples. The present critical review gives an overview of the syntheses and most important applications of polyamino polycarboxylic BFCAs (334 references).

The synthesis and application of polyamino polycarboxylic bifunctional chelating agents

NODAPA-OH and NODAPA-(NCS)n: synthesis, 68Ga-radiolabelling and in vitro characterisation of novel versatile bifunctional chelators for molecular imaging

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer).d-Methamphetamine is associated with more intense stimulanteffects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (2)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods: d- and l-methamphetamine and (2)-cocaine were labeled with 11 C via alkylation of the norprecursors with 11 C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2‐3 h apart to determine the distribution and kinetics of 11 C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11 C-d-Methamphetamine pharmacokinetics were compared with 11 C-l-methamphetamine and 11 C-(2)-cocaine in both brain and peripheral organs in the same animal. Results: 11C-d -a ndl-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11 C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11 C-d-methamphetamine and 11 C-(2)-cocaine showed that 11 C-d-methamphetamine peaked later in the brain than did 11 C-(2)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for 11C-d-methamphetamine. Conclusion:Brainpharmacokineticsdidnotdifferbetweend-and l-methamphetamineandthuscannotaccountforthemoreintense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade bymethamphetamine indicates thatthe PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of 11 C-d-methamphetamine and 11 C-(2)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (2)cocaine.High kidneyuptakeofd-methamphetamine or its labeled metabolites may account for the reportedrenal toxicityofd-methamphetamine in humans.

https://jnm.snmjournals.org/content/jnumed/48/10/1724.full.pdf

Carsten Kroll

Papers

NODAPA-OH and NODAPA-(NCS)n: synthesis, 68Ga-radiolabelling and in vitro characterisation of novel versatile bifunctional chelators for molecular imaging

PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (—)-Cocaine