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Positron Emission Tomography (PET) Replacements with Hyperpolarisable N-Methoxybenzylphenethylamines (NBOMe’s)

Marron, Jack (2021) Positron Emission Tomography (PET) Replacements with Hyperpolarisable N-Methoxybenzylphenethylamines (NBOMe’s). Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

N-methoxybenzylphenethylamines (NBOMe) were first synthesised and published in Ralf Heim’s thesis in 2003,1 detailing the selectivity of these compounds towards serotonin receptors (5-HT2A). This thesis details the full synthesis of seven phenethylamines (10 – 93 % yield as their hydrochlorides) and their transformation into the corresponding NBOMe’s (27 – 74 % yield as their hydrochlorides) with full characterisation to compare against literature. The synthesis of 21 novel derivatives (containing either a 3-pyridylmethyl-, 5-fluoro-3-pyridylmethyl- or 4-methoxy-3- pyridylmethyl- moiety) was achieved via reductive amination (3 – 18 % yield as their hydrochlorides), which were evaluated in Signal Amplification By Reversible Exchange (SABRE) Hyperpolarisation experiments in their free-base forms. A GC-MS method has be developed and achieves separation of eight NBOMe’s in 11 minutes with Limits of Detection (LoD) and Quantification (LoQ) of 6.2 – 10.8 µg mL-1 and 18.8 – 32.6 µg mL-1 respectively. The developed method has been validated against simulated blotters impregnated with the NBOMe’s and directly compared against ATR�FTIR and presumptive (Marquis and Lieberman) colour tests. SABRE Hyperpolarisation was explored using the 3-pyridylmethyl-, 5-fluoro-3- pyridylmethyl- or 4-methoxy-3-pyridylmethyl-containing derivatives, and achieved 1H and enhancements, via a low field (60 MHz) NMR, of 2x – 192x – where the best enhancement was observed in the 25B-NBOMe derivative where the 2- methoxybenzyl- group was replaced with a 4-methoxy-3-pyridylmethyl- moiety. These preliminary results indicate the potential for further development of these compounds as possible agents for medical imaging.

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