Short communication Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin Thomas M. Behr 1 , Niels Jenner 1 , Sven Radetzky 1 , Martin Béhe 1 , Stefan Gratz 1 , Selçuk Yücekent 1 , Friedhelm Raue 2 , Wolfgang Becker 1 1 Department of Nuclear Medicine, Georg-August-University, Göttingen, Germany 2 Department of Endocrinology, Ruprecht-Karl-University, Heidelberg, Germany &misc:Received 19 December 1997 and in revised form 6 January 1998 &p.1:Abstract. The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastat- ic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioio- dinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the hu- man MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastat- ic MTC. At a peptide amount of approximately 1 μg, maximum tumour uptake (8.9±2.9%ID/g) was observed in animals at 1 h post injection, with tumour-to-blood ratios as high as 6.3±1.9. Physiological CCK-B recep- tors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with 131 I-la- belled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was ob- served in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diag- nosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents po- tentially useful candidates for in vivo scintigraphy and radionuclide therapy. &kwd:Key words: Cholecystokinin-B receptor – Gastrin – Medullary thyroid cancer – Small cell lung cancer – Peptide Eur J Nucl Med (1998) 25:424–430 Introduction Regulatory peptides as tools to visualize and treat malig- nant neoplasms have been the focus of interest over re- cent years [1, 2]. The successful development of suffi- ciently stable, radiolabelled somatostatin analogues, such as 123 I-Tyr 3 - and 111 In-DTPA-D-Phe 1 -octreotide, for diagnostic purposes [1, 2], as well as the introduction of 161 Tb-DTPA or 90 Y-DOTA conjugates for therapy, has opened new horizons in nuclear oncology [3, 4]. More recently, other regulatory peptides, such as vasoactive in- testinal polypeptide (VIP) or substance P, have emerged as potentially useful candidates [5, 6]. Unlike in other neuroendocrine tumours, somatostatin receptor expression, and thus 111 In-octreotide uptake, is rather low in medullary thyroid cancer (MTC), with the consequence of a broad range of reported sensitivities [1, 7, 8]. Furthermore, we recently provided evidence in vivo that the level of somatostatin receptor expression is inversely correlated to the degree of tumour differentia- tion, as had previously been suggested in vitro on the ba- sis of receptor autoradiographic studies [9]. Whereas a comparatively high density of somatostatin receptors is present in well-differentiated forms of MTC, the com- plete loss of somatostatin receptor expression, and thus of 111 In-octreotide uptake, was demonstrated in clinical- ly aggressive, rapidly progressing forms [8, 9]. These findings serve to discourage therapeutic attempts with radiolabelled somatostatin analogues in MTC. European Journal of Nuclear Medicine Vol. 25, No. 4, April 1998 – © Springer-Verlag 1998 Correspondence to: T.M. Behr, Department of Nuclear Medicine, Georg-August-University, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany&/fn-block: