In vivo muscarinic binding of 3-(alkylthio)-3-thiadiazolyl tetrahydropyridines

Abstract

Based on encouraging in vitro data indicating M2 subtype selectivity, we synthesized, radiolabeled with 18F, and evaluated 3-(3-(2-fluoroethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetr ahydro-1-methylpyridine [FE-TZTP], and 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tet rahydro-1-methylpyridine [FP-TZTP] for muscarinic subtype selectivity in vivo. [18F]FE-TZTP displays high uptake in vivo but is inhibited only weakly by coinjecting unlabeled P-TZTP. Contrarily, [18F]FP-TZTP shows significant inhibition of uptake by coinjecting unlabeled P-TZTP or the muscarinic agonist L-687,306 (3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane ). Using in vivo autoradiography, [18F]FP-TZTP displays regional distribution consistent with M2 subtype distribution. In addition, [18F]FP-TZTP shows specific uptake in the heart at 5 min. Analysis of metabolites in the awake rat brain revealed that the parent compound represents >95% of the extractable activity at 30 min. In vivo studies in rhesus monkeys revealed rapid brain uptake of [18F]FP-TZTP, with clearance sustained over 2 h. Administration of P-TZTP or FP-TZTP (80 nmol/kg) at 60 min after injection of [18F]FP-TZTP results in a significant displacement of brain activity in all regions. Metabolite analysis in monkey plasma shows that parent compound represents 20% of the extractable radioactivity at 40 min postinjection. One metabolite, which increases with time, has similar lipophilicity to the parent. However, based on metabolism in rat we believe metabolites are not in the brain to any significant extent in monkeys during the time of imaging studies. Regional uptake, autoradiographic distribution, and clearance rates in the brain are consistent with the hypothesis that [18F]FP-TZTP is M2 selective in vivo.

2-[ 18 F]Fluoroethyl tosylate – a versatile tool for building 18 F-based radiotracers for positron emission tomography

“…in 2-[ 18 19,20 Acknowledging that application of HPLC-purified [ 18 F]FETs had a significant impact on the labeling yield, chemical and radiochemical purity of the final radiotracer 13,44 has triggered the development of innovative automated methods for production and purification of [ 18 [28][29][30][31] and equally in the [ 18 F]fluoroethylation of other amino acids like methionine and tryptophan. 33,73,[104][105][106] In radiotracer building, the reaction with [ 18 F]FETs is indispensable as has been demonstrated for a multitude of Oand N-[ 18 F]fluoroethylations, the radiolabeling of thiols 106,107,109 and the formation of [ 18 F]fluoroethyl-carboxylic esters, [63][64][65][66]102 -amides 89 and -phosphorus esters. 109,110 By…”

“…12,46,48,71 [ 18 F]FETs has been approved as a building block in the synthesis of clinically relevant radiotracers such as 2-[ 18 F]fluoroethylcholine ([ 18 F]FEC) 67,67a,b,68,69 and O-(2-[ 18 F]fluoroethyl)tyrosine ([ 18 F]FET) [28][29][30][31] and equally in the [ 18 F]fluoroethylation of other amino acids like methionine and tryptophan. 33,73,[104][105][106] In radiotracer building, the reaction with [ 18 F]FETs is indispensable as has been demonstrated for a multitude of Oand N-[ 18 F]fluoroethylations, the radiolabeling of thiols 106,107,109 and the formation of [ 18 F]fluoroethyl-carboxylic esters, [63][64][65][66]102 -amides 89 and -phosphorus esters. 109,110 By comparison of [ 18 F]FETs with other [ 18 F]fluoroalkylating reagents such as 2-[ 18 F]fluoroethyl bromide, in majority, [ 18 F]FEBr showed higher RCY but this benefit is diminished by the need of additional efforts for purification (distillation) of [ 18 F]FEBr.…”

“…65). 107 The radiosynthesis was performed as follows: after the preparation of [ 18 F]FETs, it was transferred without purification to the thiol precursor in DMF, which was deprotonated with 8 M KOH; after heating at 100°C for 5 min and semipreparative HPLC purification, [ 18 F]FE-TZTP was provided within a synthesis time of 80 min in 22% overall RCY. Furthermore, diaryl methylguanidine derivatives were found to have high affinity and selectivity to the NMDA receptor and be suitable for radiolabeling through [ 18 F]fluoroalkylation by Robins et al 108 [ 18 F]FETs was used without purification to react with the thiol-substituted guanidine precursor in the presence of Cs 2 CO 3 in acetonitrile at 110°C (Fig.…”

“…65). 107 The radiosynthesis was performed as follows: after the preparation of [ 18 F]FETs, it was transferred without purification to the thiol precursor in DMF, which was deprotonated with 8 M KOH; after heating at 100 °C for 5 min and semipreparative HPLC purification, [ 18 F]FE-TZTP was provided within a synthesis time of 80 min in 22% overall RCY.…”

Open‐source flow setup for rapid and efficient [18F]fluoride drying for automation of PET tracer syntheses

“…A description of the design of the fluoride-drying module is illustrated below: 6). [20][21][22][23] As a base for the module, a 2 mm thick aluminum plate was used, which is partially reinforced on the outside with aluminum profiles. The framework and nonelectronic components of the control unit were 3D printed (Figure 4).…”