Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats.

Methcathinone (MCAT; 1), the progenitor of numerous and widely abused "synthetic cathinone" central stimulants, exists as a pair of optical isomers. Although S(-)MCAT is several-fold more potent than R(+)MCAT in rodent locomotor stimulation and in stimulus generalization studies in rat drug discrimination assays, the individual optical isomers of MCAT have never been directly compared for their actions at monoamine transporters that seem to underlie their actions and have never been examined for their relative abuse potential. Here, we found that the isomers of MCAT are nearly equieffective at dopamine and norepinephrine transporters (DAT and NET, respectively) as transporter substrates (i.e., as releasing agents) and are ≥63-fold less potent at the serotonin transporter (SERT). In intracranial self-stimulation (ICSS) studies to evaluate abuse-related drug effects in rats, S(-)MCAT was approximately twice as potent as its R-enantiomer. Achiral analogs, α-methyl MCAT (3) and α-des-methyl MCAT (4), also were DAT/NET substrates and also produced abuse-related ICSS effects, indicating that they retain abuse potential and that they might be useful for the further study of the stereochemistry of synthetic cathinone analogs with chiral ß- (or other) substituents.

Clinical and radiobiological evaluation of a method for planning target volume generation dependent on organ-at-risk exclusions in magnetic resonance imaging-based prostate radiotherapy.

BACKGROUND AND PURPOSE: Due to a smaller target volume when delineating prostate on magnetic resonance imaging (MRI), margins may be too tight as compared to computed tomography (CT) delineation, potentially reducing tumor control probability (TCP) in prostate radiotherapy. This study evaluated a clinically implemented MRI-based target expansion method to provide adequate margins yet limit organ-at-risk (OAR) dose as compared to CT-based delineation. METHODS AND MATERIALS: Patients in this study were treated to 79.2 Gy in 44 fractions via intensity modulated radiotherapy using an MRI-based expansion method, which excluded OARs when performing a 5 mm isotropic (except 4 mm posterior) expansion from gross tumor volume to clinical target volume (CTV), followed by an isotropic 5 mm expansion to generate the planning target volume (PTV). Ten cases were re-planned using CT-delineated prostate with CTV-to-PTV expansion of isotropic 8 mm, except for a 5 mm posterior expansion, with comparison of PTV volumes, TCP and normal tissue complication probability (NTCP) to the MRI-based method. Under IRB approved protocol, we retrospectively evaluated 51 patients treated with the MRI-based method for acute bladder and rectal toxicity with CTC-AE version 4.0 used for scoring. RESULTS: MRI-based PTV volume differed by 4% compared to CT-based PTV volume. Radiobiological calculated TCP of the MRI-based method was found comparable to CT-based methods with an average equivalent uniform dose of 80.5 Gy and 80.1 Gy respectively. Statistically significant decrease in bladder NTCP (toxicity Grade 2 and above for 5% complications within 5 years post radiotherapy) was observed in the MRI-based method. Outcomes data collected showed 65% and 100% of patients studied experienced Grade 0/1 bladder and rectal acute toxicity respectively. Grade 2 bladder toxicity was indicated in the remaining 35% of patients studied with no Grade 3 toxicity reported. CONCLUSIONS: Results showed comparable PTV volume with MRI-based method, and NTCP was reduced while maintaining TCP. Clinically, bladder and rectal toxicities were observed to be minimal.