TSPO is an evolutionarily well-conserved 18 kDa protein consisting of 169 amino acids,1 which is mainly located at the contact sites between the outer and inner mitochondrial membranes,although it is also expressed at low levels in other subcellular compartments, such as plasma membranes and nuclear fraction of cells.2
TSPO is involved in a variety of biological processes including cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions.
TSPO is widely expressed throughout the body, with higher levels in steroid producing tissues, but also in other peripheral tissues including liver, heart, kidney, lung, immune system.
TSPO is altered in different pathological conditions. Indeed it is up-regulated in various form of brain injury and inflammation, in neuropathologies and in cancer. Furthermore a decrease in TSPO levels has been found in generalized anxiety and mood disorders. Consequently, TSPO has been suggested as a promising diagnostic marker for the evaluation of the state and progression of related diseases.
[11C]PK11195 was the first tracer to be consistently used in PET imaging studies of neuroinflammation, although numerous limitations have been pointed out, including a high level of non specific binding, and a poor signal-to-noise ratios which complicate its quantification.3 Subsequently, many groups worldwide were actively engaged in a search for TSPO ligands with improved capacities to quantify TSPO expression.
In this thesis work it has been prepared the sulfoxide precursor of [18F](R)-PK14105. The isoquinolinecarboxamide, PK14105, has been previously labelled with fluorine-18 (t1/2 – 109.7 min)
and evaluated in rat as a prospective radiotracer for imaging human TSPO 18 kDa with PET. This radiotracer initially appeared promising, but extensive evaluation was hindered by its rather difficult radiosynthesis based on substitution of a chloro-substituent with cyclotron–produced [18F]fluoride ion. Recently, it has been shown that simple p-nitroarylsulfoxides react readily with [18F]fluoride ion to produce the corresponding [18F]p-nitrofluoroarenes in good radiochemical yields.
1. Gavish, M.; Bachman, I.; Shoukrun, R.; Katz, Y.; Veenman, L.; Weisinger, G.; Weizman. Pharmacol. Rev. 1999, 51, 619-640.
2. Papadopoulos, V.; Baraldi, M.; Guilarte, T.R.; Knudsen, T.B.; Lacapère, J.; Lindemann, P.; Norenberg, M.D.; Nutt, D.; Weizman, A.; Zhang, M.-R.; Gavish, M. Trends Pharmacol. Sci. 2006, 27, 402-409.
3. Venneti, S.; Wiley, C.A. Prog. Neurobiol. 2006, 80, 308-322.
N N O S O2N N N O [18F]KF 18F DMSO or DMF O2N [18F](R)-PK14105 O
