Somatostatin (SRIF) is a neurotransmitter in the brain. Subtypes of SRIF receptors may mediate the diverse physiological actions of SRIF in the central nervous system. In the present study, the characteristics of subtypes of brain SRIF receptors were examined using two SRIF analogs. [125I]CGP 23996 and [125I]MK 678. [125I]CGP 23996 binds selectively to rat brain SRIF receptors in a saturable manner and with high affinity. [125I]CGP 23996 binding to brain SRIF receptors is inhibited by SRIF agonists with a rank order of potency of SRIF greater than cyclo (aha-Cys-Phe-D-Trp-Lys-Thr-Cys) greater than SMS 201-995 much greater than MK 678 = L-363,301. [125I]MK 678 labels rat brain SRIF receptors which are not detected by low nanomolar concentrations of [125I]CGP 23996. [125I]MK 678 binding to brain membranes is saturable and of high affinity with a Kd of 0.3 nM and a Bmax of 217 fmol/mg of protein in brain and a Kd of 0.17 nM and a Bmax of 211 fmol/mg of protein in anterior pituitary. [125I]MK 678 binding to brain SRIF receptors is blocked selectively by SRIF analogs. SRIF, SRIF 28, D-Trp8 SRIF, SMS 201-995, cyclo (aha-Cys-Phe-D-Trp-Lys-Thr-Cys) and MK 678 have similar potencies to inhibit [125I]MK 678 binding to brain SRIF receptors. The different rank order of potencies of SRIF analogs to inhibit [125I]CGP 23996 and [125I]MK 678 binding to brain SRIF receptors suggests that these radioligands interact with different subtypes of brain SRIF receptors.(ABSTRACT TRUNCATED AT 250 WORDS)