Evaluation of [C-11]GB67, a novel radioligand for imaging myocardial alpha(1)-adrenoceptors with positron emission tomography

Dysfunction of the sympathetic nervous system underlies a number of myocard ial disorders. Positron emission tomography (PET) offers a way of assess -i ng receptor function non-invasively in humans, but there are no PET radioli gands 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-met hylation of N-desmethylamido-GB67 (GB99). [C-11]GB67 was injected intraveno usly into conscious nts, Serial arterial blood samples were taken. Rats wer e 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. Myocar dial uptake was maximal at 1-2 min and decreased slowly during 60 min. Pred osing 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 do se and the beta-adrenoceptor antagonist, CGP 12177, had no effect. Addition ally, injection of prazosin at 20 min after radioligand displaced radioacti vity. In vivo competition curves obtained by injecting [C-11]GB67 with vary ing amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of b inding 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 precu rsor 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 demonstrat ed four radioactive metabolites in plasma. [C-11]GB67 was 80% of the radioa ctivity at 5 min and 50% at 45 min. No radioactive metabolites were detecte d in myocardium up to 60 min after injection. [C-11]GB67 was assessed in tw o male human volunteers. PET demonstrated high myocardial uptake. The profi le 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 r adioligand for assessing alpha(1)-adrenoceptors in human myocardium with PE T.