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A(14)-Iodoinsulin is a close biochemical and pharmacological mimic of insulin. Human insulin was labelled in its A chain tyrosine-14 residue by direct iodination with the positron-emitter iodine-124 (beta (+) = 25.6%; t(1/2) = 4.15 days) to provide a radiotracer for imaging with positron emission tomography (PET). Several reagents were compared for conversion of cyclotron-produced [I-124]iodide into a reactive species for the labelling reaction. Radiochemical yields from the use of Iodo-Gen (R), Chloramine-T, N-bromosuccinimide or lactoperoxidase-hydrogen peroxide were similar [35% (n = 1), 33 +/- 9% (n = 10), 32 +/- 11% (n = 25) or 33% (n = 2), respectively]. [I-124]A(14)-Iodoinsulin was separated from unreacted insulin and radioactive by-products by tandem reverse phase HPLC and rapidly formulated for intravenous injection by adsorption on a Sep-Pak (t)C18-Plus (R) cartridge, followed by elution with 10 mM hydrochloric acid-ethanol (1 : 1 v/v, 1 mi). This radiotracer can now be obtained in useful radioactivities at high effective specific radioactivity and is now being applied to PET studies of its biodistribution in living subjects. Copyright (C) 2001 John Wiley & Sons, Ltd.

We studied the uptake of propionyl-L-carnitine from plasma by the myocardium in 10 human subjects using positron emission tomography. Propionyl-L-carnitine was labeled in the N-methyl position with carbon-11 (T 1/2 = 20 4 min) and administered i.v. in trace amounts. The uptake of the radiolabel by the myocardium was then scanned over a period of 1 1/2 h. The activity-time course of the tracer in blood and plasma and the exchange of the label in plasma between propionyl carnitine, acetyl carnitine and free carnitine was followed during the scans. Myocardial blood flow was also measured in the same subjects. The results show an exchange of the tracer between the myocardium and plasma, and they show an apparently irreversible component of uptake, a result consistent with the incorporation of the label into relatively large intracellular carnitine pools.

Dysfunction of the sympathetic nervous system underlies a number of myocardial disorders. Positron emission tomography (PET) offers a way of assess -ing receptor function non-invasively in humans, but there are no PET radioligands for assessing myocardial alpha-adrenoceptors. GB67, a structural and pharmacological analogue of the alpha(1)-adrenoceptor antagonist prazosin, was labelled with positron-emitting carbun-11 (t(1/2)=20.4 min) by C-11-methylation of N-desmethylamido-GB67 (GB99). [C-11]GB67 was injected intravenously into conscious nts, Serial arterial blood samples were taken. Rats were killed and tissues removed to determine radioactivity. The percentages of unchanged [C-11]GB67 and its radioactive metabolites in plasma and tissues were assessed by HPLC, Plasma clearance of radioactivity was rapid. Myocardial uptake was maximal at 1-2 min and decreased slowly during 60 min. Predosing with adrenoceptor antagonists demonstrated selectivity for myocardial alpha(1)-adrenoceptors. GB67 and prazosin blocked uptake of radioactivity; the non-selective antagonist, phentolamine, partially blocked uptake; the alpha(2)-adrenoceptor antagonist, RX 821002, only blocked uptake at high dose and the beta-adrenoceptor antagonist, CGP 12177, had no effect. Additionally, injection of prazosin at 20 min after radioligand displaced radioactivity. In vivo competition curves obtained by injecting [C-11]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of binding sites (B-max) and half saturation doses (K) for myocardium. Assuming a tissue protein content of 10%, the values of B-max [similar to 13 pmol.(g tissue)(-1)] were similar to those [50-170 fmol(mg protein)(-1)] reported for myocardial al-adrenoceptors assessed in vitro. Both GB67 and its precursor GB99 had high affinity for alpha(1)-adrenoceptors [K-GB67=1.5 nmol.(kg body weight)(-1), K-GB99=4.8 nmol . (kg body weight)(-1)]. HPLC demonstrated four radioactive metabolites in plasma. [C-11]GB67 was 80% of the radioactivity at 5 min and 50% at 45 min. No radioactive metabolites were detected in myocardium up to 60 min after injection. [C-11]GB67 was assessed in two male human volunteers. PET demonstrated high myocardial uptake. The profile of radioactive metabolites in plasma was comparable to that in the rat, although metabolism was slower in humans. Thus, [C-11]GB67 is a promising radioligand for assessing alpha(1)-adrenoceptors in human myocardium with PET.