The Story of the Dopamine Transporter PET Tracer LBT-999: From Conception to Clinical Use

Abstract

The membrane dopamine transporter (DAT) is involved in a number of brain disorders and its exploration by positron emission tomography (PET) imaging is highly relevant for the early and differential diagnosis, follow-up and treatment assessment of these diseases. A number of carbon-11 and fluor-18 labeled tracers are to date available for this aim, the majority of them being derived from the chemical structure of cocaine. The development of such a tracer, from its conception to its use, is a long process, the expected result being to obtain the best radiopharmaceutical adapted for clinical protocols. In this context, the cocaine derivative (E)-N -(4-fluorobut-2-enyl)2β-carbomethoxy-3β-(4′-tolyl)nortropane, or LBT-999, has passed all the required stages of the development that makes it now a highly relevant imaging tool, particularly in the context of Parkinson's disease. This review describes the different steps of the development of LBT-999 which initially came from its non-fluorinated derivative ( E )- N -(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methylphenyl) nortropane, or PE2I, because of its high promising properties. [ 18 F]LBT-999 has been extensively characterized in rodent and non-human primate models, in which it demonstrated its capability to explore in vivo the DAT localized at the dopaminergic nerve endings as well as at the mesencephalic cell bodies, in physiological conditions. In lesion-induced rat models of Parkinson's disease, [ 18 F]LBT-999 was able to precisely quantify in vivo the dopaminergic neuron loss, and to assess the beneficial effects of therapeutic approaches such as pharmacological treatment and cell transplantation. Finally recent clinical data demonstrated the efficiency of [ 18 F]LBT-999 in the diagnosis of Parkinson's disease.

Determination of Parameter Reference Values for 18F-DOPA PET Imaging of the Brain (Based on Using Data from Healthy Subjects)

“…18 F-DOPA обеспечивает эффективное решение задач ранней диагностики БП, но, как отмечено выше, распространенность этого препарата в медицинских исследованиях в настоящее время невысока. Разрабатываются также другие РФП, одним из наиболее перспективных считается [ 18 F]LBT-999 -производное кокаина [5]. 18 F-DOPA, являясь аналогом леводопы, связывается с декарбоксилазой ароматических аминокислот и генерирует позитронный выброс.…”

[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease

“…Diagnostic, molecular imaging is a valuable tool to evaluate movement disorder patients, and in addition to [ 123 I]FP-CIT, new, specific PET tracers have emerged in recent years. 21 – 23 Related to the advantages mentioned previously of PET over SPECT, 18 those might improve diagnostic accuracy or even serve as predictive markers. This was exemplified in a recent study demonstrating that anterior-to-posterior gradient and right-to-left asymmetry of striatal DAT availability, measured by [ 18 F]FP-CIT-PET, predicted the development of levodopa-induced dyskinesia.…”

“… 19 , 20 Several promising 18 F-labeled PET imaging compounds, such as [ 18 F]FP-CIT, [ 18 F]FE-PE2I, and [ 18 F]LBT-999, have been developed but are still in early clinical development. 17 , 21 – 23 …”

Next-Generation Diamond Electrodes for Neurochemical Sensing: Challenges and Opportunities

“…Detection methods for sensing neurochemicals in vivo for the study of neurological disorders would ideally be simultaneously sensitive, minimally-invasive, chronically stable, and relatively inexpensive. In a recent review by S. Niyonambaza et al, techniques for neurotransmitter (NT) identification and quantification were discussed in depth [ 28 ], including positron emission tomography and single photon NT identification and measurement [ 29 , 30 , 31 ], single-photon emission computed tomography [ 32 , 33 ], surface-enhanced Raman spectroscopy [ 34 , 35 ], fast-scan cyclic voltammetry (FSCV) [ 36 , 37 , 38 ], amperometry [ 39 , 40 ], high performance liquid column chromatography (HPLC) [ 41 , 42 , 43 ], fluorescence [ 44 , 45 ], optical fiber sensing [ 46 , 47 ], and colorimetric measurements [ 48 , 49 , 50 ], as seen in Table 1 . Longitudinal positron emission tomography (PET), while non-invasive, is not adequately sensitive to detect subtle changes in dopamine (DA) levels.…”