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K A Jaeggi

Publications and source records attributed to K A Jaeggi.

11 recordsLinked to original sources
PubMed1998

A novel beta-adrenoceptor ligand for positron emission tomography: evaluation in experimental animals.

Myocardial and pulmonary beta-adrenoceptors can be imaged and quantified with the antagonist (S)-4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-b enzimidazol-2-[11C]-one (S-[11C]CGP-12177). The synthesis of this ligand (based on the reaction of a precursor with [11C]phosgene) is laborious and in many centers the final product has a low and variable specific activity. This prevents widespread use of S-[11C]CGP-12177 for studies in patients. We prepared S-[11C]CGP-12388, the isopropyl analogue of CGP-12177, by a reliable one-pot procedure and evaluated the radiopharmaceutical for beta-adrenoceptor imaging. Blocking experiments with subtype-selective beta-adrenergic drugs showed that myocardial and pulmonary uptake of S-[11C]CGP-12388 in anesthetized rats reflects ligand binding to beta1- and beta2-adrenoceptors. In this animal model, clearance, metabolism and tissue/plasma ratios of S-[11C]CGP-12388 were similar to those of S-[11C]CGP-12177. A [18F]fluoroisopropyl analogue of CGP-12177 showed less favorable characteristics. S-[11C]CGP-12388 was therefore selected for evaluation in humans and it may become the tracer of choice for clinical studies since it is easily prepared.

Adrenergic beta-Antagonists↗
PubMed1997

Synthesis and evaluation of (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol -2-one ((S)-[11C]CGP 12388) and (S)-4-(3-((1'-[18F]-fluoroisopropyl)amino)-2-hydroxypropoxy) -2H- benzimidazol-2-one ((S)-[18F]fluoro-CGP 12388) for visualization of beta-adrenoceptors with positron emission tomography.

The beta-adrenoceptor antagonist (S)-[11C]CGP 12177 (4-(3-(tert-butylamino)-2-hydroxypropoxy)-2H-benzimidazol -2[11C]- one) is a generally accepted radioligand for cardiac and pulmonary PET studies. The synthesis of [11C]CGP 12177 is a laborious and often troublesome procedure. Therefore, (S)-CGP 12388 (4-(3-(isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol-2-one), 5, the isopropyl analogue of CGP 12177, has been labeled with carbon-11 in the isopropyl group via a reductive alkylation by [11C]acetone (3) of the corresponding (S)-desisopropyl compound 2. The fluoro-substituted analogue of (S)-CGP 12388 was prepared by reacting 2 with [18F]fluoroacetone (4). (S)-[11C]CGP 12388 (5) was easily prepared via a one-pot procedure. The radiochemical yield of (S)-[11C]CGP 12388 (600-800 Ci/mmol, EOS) was 18% (EOB) with a total synthesis time of 35 min, whereas (S)-[18F]fluoro-CGP 12388 (6) (> 2000 Ci/mmol, EOS) was synthesized in 105 min with a radiochemical yield of 12% (EOB). Biodistribution studies in rats demonstrated specific binding to beta-adrenoceptors of (S)-[18F]fluoro-CGP 12388 and (S)-[11C]CGP 12388 in lung and heart. The lungs were clearly visualized with PET studies of rats. Total/nonspecific binding at 60 min postinjection was 5.6 for (S)-[11C]CGP 12388 and 2.0 for the (S)-18F compound. Due to its facile synthetic procedure and in vivo data, (S)-[11C]CGP 12388 is a promising beta-adrenoceptor ligand for clinical PET.

Adrenergic beta-Antagonists↗
PubMed1997

Renal tolerability profile of novel, potent bisphosphonates in two short-term rat models.

Bisphosphonates are used clinically to inhibit bone resorption but they may also cause renal damage. For the profiling of new potent bisphosphonates, their adverse renal effects were investigated in 2 rat models. In the first model, bisphosphonate was repeatedly injected (1 mg/kg, subcutaneously) over 2 weeks and the urinary excretion of malate dehydrogenase was monitored to assess nephrotoxic potential. Of the 6 new compounds tested, 3 markedly elevated malate dehydrogenase whereas 3 others caused only minor changes similar to those observed with 6 reference bisphosphonates that are already used clinically. On the basis of a therapeutic index (inhibition of bone resorption versus renal effects) 7-180 fold greater than that of other analogues, the compound CGP 42446 was further profiled. In the second model, CGP 42446 or pamidronate was infused (1.5-50 mg/kg, intravenously) into anaesthetized rats and the serum urea concentration was monitored as an indicator of renal dysfunction. Both compounds elevated serum urea in a time- and dose-dependent manner, but the ED100 value for CGP 42446 was 3.8-fold higher than that of pamidronate. It is concluded that CGP 42446 (zoledronate) has a low nephrotoxic potential and can be further developed as a new potent inhibitor of bone resorption.

Animals↗
PubMed1994

Synthesis and properties of fluorescent beta-adrenoceptor ligands.

We describe the synthesis of bordifluoropyrromethene (BODIPY), fluorescein, and related fluorescent derivatives of the beta-adrenergic ligand CGP 12177. With these probes we screened insect (Sf9) cells stably transformed with the human beta 2-adrenoceptor gene and expressing (2-3.5) x 10(5) human beta 2-adrenoceptors per cell. Among these derivatives only BODIPY-CGP gave a receptor-specific signal sufficiently strong for measuring the on- and off-rate constants and the equilibrium dissociation constant of beta-adrenoceptor-specific binding by spectrofluorometry or photon counting. Similar KD values for BODIPY-CGP binding were obtained by kinetic measurements (approx. 250 pM) and under equilibrium conditions (400 +/- 180 pM), and these were in the same range as those obtained with [3H]CGP 12177 (200 +/- 32 pM). The cell-bound fluorescence could be quenched specifically with nonfluorescent CGP 12177 to near background levels. The disposition of the beta 2-adrenoceptors in BODIPY-CGP-stained Sf9 cells was mainly restricted to the cell surface at 4 and 30 degrees C. Hence, beta-adrenoceptor-expressing cells can be stained specifically with BODIPY-CGP, and beta-adrenoceptors on a single cell can be assessed by photon counting under the fluorescence microscope. Cells can also be scanned by fluorescence-activated flow cytometry.

Adrenergic beta-Antagonists↗
PubMed1994

Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound.

We have investigated the pharmacologic effects of a new bisphosphonate compound, CGP 42'446 [2-(imidazol-1-yl)-1-hydroxyethylidene-1,1-bisphosphonate], on bone metabolism. The compound exhibited potent inhibitory activity on the bone resorption induced by 1,25-dihydroxyvitamin D3 both in vivo in the thyroparathyroidectomized rat (ED50 0.072 microgram/kg SC) and in vitro in mouse calvarial cultures (IC50 0.002 microM). A comparison of the in vivo and in vitro inhibitory potencies of a total of nine bisphosphonates revealed an excellent correlation between the two assays (r = 0.97). CGP 42'446 also potently inhibited calvarial bone resorption induced by parathyroid hormone (1-34), parathyroid hormone-related protein (1-34), and recombinant human interleukin-1 beat. Short-term treatment of growing rats with CGP 42'H446 dose-dependently increased the radiographic density of the tibial proximal metaphysis (ED50 1.7 micrograms/kg SC) as well as increasing the calcium and hydroxyproline content of femoral trabeculae (ED50 values 0.17 and 1.1 micrograms/kg SC, respectively), but there was no detectable effect on cortical bone. On a molar basis in this range of in vivo screening assays, CGP 42'H446 was between 940-fold (thyroparathyroidectomized rat) and 87-fold (rat femoral trabecular calcium content) more potent than pamidronate. It is concluded that CGP 42'446 is a promising new, highly potent bisphosphonate for the suppression of the increased bone resorption associated with various diseases.

Animals↗
PubMed1991

Asymmetric synthesis of a precursor for the automated radiosynthesis of S-(3'-t-butylamino-2'-hydroxypropoxy)-benzimidazol-2-[11C]one (S-[11C]CGP 12177) as a preferred radioligand for beta-adrenergic receptors.

S-[1-(2,3-Diaminophenoxy)]-3'-(N-t-butylamino)propan-2'-ol has been synthesized in three steps from 2,3-dinitro-phenol and the chiral auxiliary, S-glycidyl-3-nitrobenzenesulphonate, to provide a precursor for labelling S-(3'-t-butylamino-2'-hydroxypropoxy)-benzimidazol-2-one (S-CGP 12177) with the short-lived positron-emitting radionuclide, carbon-11 (t 1/2 = 20.4 min; beta+ = 99.8%). Reaction of the diamine with [11C]phosgene, itself derived from no-carrier-added cyclotron-produced [11C]methane, provides radiochemically and chemically pure S-[carbonyl-11C]CGP 12177 in greater than 95% enantiomeric excess after HPLC. Automated apparatus is described for safely producing up to 5.9 GBq (160 mCi) of S-[11C]CGP 12177 with high sp. act. (20-40 GBq/mu mol or 0.54-1.08 Ci/mu mol) in a form suitable for human intravenous injection at only 30 min from the end of radionuclide production. S-[11C]CGP 12177 is preferred to the formerly described racemate as a radioligand for the study of beta-adrenergic receptors in vivo by positron emission tomography.

Adrenergic beta-Antagonists↗
PubMed1988

Synthesis and characterization of CGP-12177-NBD: a fluorescent beta-adrenergic receptor probe.

The synthesis and properties of a fluorescent derivative of the hydrophilic beta-adrenergic antagonist CGP-12177 are described. The fluorescence of the NBD derivative of CGP-12177 (CGP-NBD) is extremely sensitive to its environment, the quantum yield increasing 23-fold upon transfer from water to acetonitrile. This property of CGP-NBD was taken into account and a procedure was developed using quantitative chloroform extraction of ligand for the measurement of CGP-NBD bound specifically to beta-receptors on A431.E3 membranes. The fluorescent NBD-derivative of CGP-12177 bound strongly and specifically to A431 cells, a KD of 3.9 x 10(-10) M being measured; the specific binding represented 63% of the total binding at a concentration of 1 x 10(-8) M (256 x KD). A431.E3 cells were used for the binding studies since they gave consistently higher receptor numbers when compared with the native strain. A maximal number of 47,000 sites/cell and a KD of 100 pM were measured with CGP-12177 on adhered cells. The receptor number was strongly dependent upon cell density with only 3000 sites/cell being measured in suspension at confluence.

4-Chloro-7-nitrobenzofurazan↗