Recently, the development of the fluorinated PET tracer [F]1a for imaging of CB receptors in the central nervous system was reported. [F]1a showed high CB affinity and selectivity over the CB subtype, but rapid biotransformation in mice. In addition to the amide hydrolysis, oxidative N-dealkylation and carbazole oxidation were postulated as main metabolic pathways. Based on these results, novel carbazole derivatives with additional 6-substituents (23a, 24a), modified hydrogenation state (26a) and enlarged fluoroalkyl substituent (13a, 13b) were synthesized and pharmacologically evaluated. The key step in the synthesis of substituted carbazoles 23a, 24a and 26a was a Fischer indole synthesis. Nucleophilic substitution of tosylated lactate 5 by carbazole anion provided the fluoroisopropyl derivatives 13a and 13b. Partial hydrogenation of the aromatic carbazole system (26a) was not tolerated by the CB receptor. A methylsulfonyl moiety in 6-position (24a) led to considerably reduced CB affinity, whereas a 6-methoxy moiety (23a) was well tolerated. An additional methyl moiety in the fluoroethyl side chain of 1a resulted in fluoroisopropyl derivatives 13 with unchanged high CB affinity and CB: CB selectivity. Compared with the fluoroethyl derivative 1a, the carbazole N-atom of the fluoroisopropyl derivative 13a (K(CB) = 2.9 nM) is better shielded against the attack of CYP enzymes as formation of N-oxides was not observed and N-dealkylation took place to a less amount.

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Calcified cerebral necrosis was an unusual finding at the autopsy of a 13-year-old girl who died after prolonged therapy for ALL. The patient had shown symptoms of progressive cerebral damage subsequent to a second cycle of prophylactic high-dose cytostatic therapy combined with cranial irradiation. Pathoanatomic examination revealed extensive florid recurrency of meningosis and leukemic encephalosis with scalloped calcified necroses measuring up to 5 cm, in the medullar layer of brain and cerebellum. Located predominantly near the ventricular area, encapsulated necroses showed many fibrous vessels with thickened walls and stenosed or obstructed lumina. The cerebral cortex remained largely unaffected by tissue destruction. Besides methotrexate toxicity and the enhancing effect of irradiation the vascular involvement was interpreted as a particularly important factor. Formal pathogenesis is attributed to combined chemo- and radiotherapy in parallel to leukemic infiltration of vascular walls and partial obstruction of lumina by tumor emboli. Wall damage, severe fibrosis, and consecutive nutritional defects result in the destruction of cerebral tissue. The preferential occurrence of necroses in cortex-adjacent medullar layers is explained by the relatively poor blood supply of this border zone between meningeal and intracerebral tissue, no safe conclusion can be drawn pathoanatomically with regard to the actually fatal factor, whether it is the leukemic infiltration of vascular walls, the effect of cytostatic agents, or that of irradiation. The proposed multifactorial pathogenesis of cerebral calcification may be supported by computed tomography (CT) intra vitam.