[en] The prospective therapeutic, propionyl-l-carnitine, was labelled in the N-methyl position with the positron-emitter, carbon-11 (t₍₁₍₂₎₎ = 20.4 min), with a view to studying its pharmacokinetics in humans using PET. Labelling was achieved by methylating nor-propionyl-l-carnitine hydrochloride with no-carrier-added [¹¹C]iodomethane (produced from cyclotron-produced [¹¹C]carbon dioxide) in ethanol in the presence of 1,2,2,6,6,-pentamethylpiperidine. HPLC of the reaction mixture on a strong cation exchange column provided high purity [N-methyl-¹¹C]propionyl-l-carnitine in 62% radiochemical yield (decay-corrected from [¹¹C]iodomethane), ready for intravenous administration within 35 min from the end of radionuclide production. [N-methyl-¹¹C]Propionyl-l-carnitine, given intravenously to rats, cleared rapidly from plasma. A slow uptake of radioactivity into myocardium and striated muscle was observed. In plasma, unchanged tracer represented 84% of the radioactivity at 2.5 min and 2.5% of the radioactivity at 60 min. In heart, unchanged tracer represented 18% of radioactivity at 2.5 min and 2.4% at 15 min. The remainder of radioactivity detected in plasma and heart was identified as [N-methyl-¹¹C]l-carnitine and [N-methyl-¹¹C]acetyl-l-carnitine

[en] Biodistribution and metabolism of [N-methyl-¹¹C]-m-hydroxyephedrine ([¹¹C]mHED), an analogue of noradrenaline, were assessed in rats. Pretreatment with desipramine, an uptake₁, blocker, reduced uptake of radioactivity in myocardium but not in lung, liver, kidney, and muscle. Brain uptake was negligible. HPLC showed six radioactive metabolites in plasma and liver but none in myocardium. Co-injection of unlabelled mHED or metaraminol with [¹¹C]mHED demonstrated no difference between the in vivo binding potentials for mHED and metaraminol in myocardium

[en] Non-invasive measurement of matrix metalloproteinase (MMP) activity in vivo is a clinical challenge in many disease processes such as inflammation, tumor metastasis and atherosclerosis. Therefore, radioiodinated analogues of the non-peptidyl broad-spectrum MMP inhibitor (MMPI) CGS 27023A 1a were synthesized for non-invasive detection of MMP activity in vivo using single photon emission computed tomography (SPECT). The compounds Br-CGS 27023A 1b and HO-CGS 27023A 1d were synthesized from the amino acid D-valine and used as precursors for radioiodinated derivatives of CGS 27023A and their non-radioactive references I-CGS 27023A 1c and HO-I-CGS 27023A 1e. Radioiodination of the precursors with [¹²³I]NaI or [¹²⁵I]NaI produced the no-carrier-added MMP inhibitors [¹²³I]I-CGS 27023A 1f, [¹²⁵I]I-CGS 27023A 1g, HO-[¹²³I]I-CGS27023A 1h, and HO-[¹²⁵I]I-CGS 27023A 1i. In vitro studies showed that the non-radioactive analogues of the MMP inhibitors exhibited affinities against gelatinase A (MMP-2) and gelatinase B (MMP-9) in the nanomolar range, comparable to the parent compound CGS 27023A. In vivo biodistribution using HO-[¹²⁵I]I-CGS 27023A 1i in CL57 Bl6 mice showed rapid blood and plasma clearance and low retention in normal tissues. The preliminary biological evaluation warrant further studies of these radioiodinated MMP inhibitors as potential new radiotracers for imaging MMP activity in vivo

[en] Molecular cardiovascular imaging plays an increasingly important role both in basic research and in clinical diagnosis. Scintigraphic methods have long been used to study pathophysiological changes on a cellular and molecular level, and they are likely to remain important molecular imaging modalities in the foreseeable future. This article provides an overview over current developments in cardiovascular molecular imaging using scintigraphic methods. The focus lies on imaging of cardiac innervation, plaque instability, hypoxia and angiogenesis, gene expression and stem and progenitor cell migration and proliferation. (orig.)

[en] Radioligand binding studies show that β₁-adrenoceptor (β₁-AR) density may be reduced in heart disease without down regulation of β₂-ARs. Radioligands are available for measuring total β-AR density non-invasively with clinical positron emission tomography (PET) but none are selective for β₁- or β₂-ARs. The aim was to evaluate ICI 89,406, a β₁-AR-selective antagonist amenable to labelling with positron emitters, for PET. The S-enantiomer of an [O-methyl-¹¹C] derivative of ICI 89,406 ((S)-[¹¹C]ICI-OMe) was synthesised. Tissue radioactivity after i.v. injection of (S)-[¹¹C]ICI-OMe (< 2 nmol.kg^-1) into adult Wistar rats was assessed by small animal PET and post mortem dissection. Metabolism was assessed by HPLC of extracts prepared from plasma and tissues and by measuring [¹¹C]CO₂ in exhaled air. The heart was visualised by PET after injection of (S)-[¹¹C]ICI-OMe but neither unlabelled (S)-ICI-OMe nor propranolol (non-selective β-AR antagonist) injected 15 min after (S)-[¹¹C]ICI-OMe affected myocardial radioactivity. Ex vivo dissection showed that injecting unlabelled (S)-ICI-OMe, propranolol or CGP 20712A (β₁-selective AR antagonist) at high dose (> 2 μmol.kg^-1) before (S)-[¹¹C]ICI-OMe had a small effect on myocardial radioactivity. HPLC demonstrated that radioactivity in myocardium was due to unmetabolised (S)-[¹¹C]ICI-OMe although ¹¹C-labelled metabolites rapidly appeared in plasma and liver and [¹¹C]CO₂ was detected in exhaled air. Myocardial uptake of (S)-[¹¹C]ICI-OMe after i.v. injection was low, possibly due to rapid metabolism in other tissues. Injection of unlabelled ligand or β-AR antagonists had little effect indicating that binding was mainly to non-specific myocardial sites, thus precluding the use of (S)-[¹¹C]ICI-OMe to assess β₁-ARs with PET. (orig.)

[en] Purpose: Radioligand binding studies indicate a down-regulation of myocardial β₁-adrenoceptors (β₁-AR) in cardiac disease which may or may not be associated with a decrease in β₂-ARs. We have chosen ICI 89,406, a β₁-selective AR antagonist, as the lead structure to develop new β₁-AR radioligands for PET and have synthesised a fluoro-ethoxy derivative (F-ICI). Methods: (S)-N-[2-[3-(2-Cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]-N'-[4-(2-[¹⁸F] fluoro-ethoxy)-phenyl]-urea ((S)-[¹⁸F]F-ICI) was synthesised. Myocardial uptake of radioactivity after intravenous injection of (S)-[¹⁸F]F-ICI into adult CD₁ mice or Wistar rats was assessed with positron emission tomography (PET) and postmortem dissection. Metabolism was assessed by high-performance liquid chromatography analysis of plasma and urine. Results: The heart was visualised with PET after injection of (S)-[¹⁸F]F-ICI but neither unlabelled F-ICI nor propranolol (non-selective β-AR antagonist) injected 15 min after (S)-[¹⁸F]F-ICI affected myocardial radioactivity. Ex vivo dissection demonstrated that predosing with propranolol or CGP 20712 (β₁-selective AR-antagonist) did not affect myocardial radioactivity. Radiometabolites rapidly appeared in plasma and both (S)-[¹⁸F]F-ICI and radiometabolites accumulated in urine. Conclusions: Myocardial uptake of (S)-[¹⁸F]F-ICI after intravenous injection was mainly at sites unrelated to β₁-ARs. (S)-[¹⁸F]F-ICI is not a suitable β₁-selective-AR radioligand for PET.

[en] Peroxisome proliferator-activated receptor-γ (PPARγ) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPARγ in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPARγ agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPARγ, glucose transporter-4 and α-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPARγ, glut-4, and α-MHC expression levels in diabetic ZDF rats. Cardiac [¹⁸F]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPARγ agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPARγ expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin